U.S. patent application number 15/576607 was filed with the patent office on 2018-07-26 for nucleotides for the treatment of cancer.
The applicant listed for this patent is Cyril B. Dousson, David Dukhan, Jean-Laurent Paparin, Chtirstophe C. Parsy. Invention is credited to Cyril B. Dousson, David Dukhan, Jean-Laurent Paparin, Chtirstophe C. Parsy.
Application Number | 20180208621 15/576607 |
Document ID | / |
Family ID | 53298297 |
Filed Date | 2018-07-26 |
United States Patent
Application |
20180208621 |
Kind Code |
A1 |
Dousson; Cyril B. ; et
al. |
July 26, 2018 |
NUCLEOTIDES FOR THE TREATMENT OF CANCER
Abstract
The present application relates to novel nucleoside derivatives
of formula (I) as claimed in claim 1, pharmaceutical compositions
comprising the compounds, processes of preparation thereof, and
methods of use thereof for treating cancer.
Inventors: |
Dousson; Cyril B.;
(Montpellier Cedex 4, FR) ; Dukhan; David;
(Montpellier Cedex 4, FR) ; Paparin; Jean-Laurent;
(Montpellier Cedex 4, FR) ; Parsy; Chtirstophe C.;
(Montpellier Cedex 4, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dousson; Cyril B.
Dukhan; David
Paparin; Jean-Laurent
Parsy; Chtirstophe C. |
Montpellier Cedex 4
Montpellier Cedex 4
Montpellier Cedex 4
Montpellier Cedex 4 |
|
FR
FR
FR
FR |
|
|
Family ID: |
53298297 |
Appl. No.: |
15/576607 |
Filed: |
May 25, 2016 |
PCT Filed: |
May 25, 2016 |
PCT NO: |
PCT/EP2016/061842 |
371 Date: |
November 22, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/02 20180101;
C07H 19/11 20130101; C07H 19/10 20130101; A61K 2121/00 20130101;
C07D 409/04 20130101 |
International
Class: |
C07H 19/11 20060101
C07H019/11; A61P 35/02 20060101 A61P035/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 27, 2015 |
EP |
15305803.7 |
Claims
1. A compounds according to Formula I: ##STR00059## or a
pharmaceutically acceptable salt thereof, wherein: one of R.sup.1
and R.sup.2 is hydrogen and the other is ##STR00060## or R.sup.1
and R.sup.2 together with the two oxygen atoms to which they are
attached form the ring structure: ##STR00061## R.sup.3 is hydrogen,
C.sub.1-10alkyl, C.sub.2-11alkenyl, C.sub.2-11alkynyl,
C.sub.1-10alkoxycarbonylC.sub.1-10alkyl,
C.sub.1-10alkylcarbonylthioC.sub.1-10alkyl,
C.sub.1-10alkyldisulfideC.sub.1-6alkyl, aryl or
heteroarylC.sub.1-10alkyl, wherein alkyl is optionally substituted
by one, two or three substituents independently selected from
halogen and hydroxy, and heteroaryl is substituted by one or two
substituents selected from C.sub.1-10alkyl and nitro; R.sup.4 is
hydrogen or C.sub.1-10alkyl; R.sup.5 is C.sub.1-10alkoxycarbonyl,
C.sub.3-10cycloalkoxycarbony,
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl,
C.sub.3-10cycloalkylcarbonyoxy, aryl, aryloxy, C.sub.1-10alkylaryl,
arylC.sub.1-10alkyl, arylC.sub.1-10alkoxycarbonyl, aryloxycarbonyl,
heteroaryl, heteroarylC.sub.1-10alkyl or C.sub.1-10alkylheteroaryl;
R.sup.6 is ##STR00062## and W is O or S, providing that the
compounds of the following formula are excluded: ##STR00063##
wherein R.sup.3' is aryl or an optionally substituted heteroaryl,
R.sup.4' is C.sub.1-10alkyl, R.sup.x is C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, arylC.sub.1-10alkyl or aryl, and W is O.
2. A compound of claim 1 wherein one of R.sup.1 and R.sup.2 is
hydrogen and the other is ##STR00064## or a pharmaceutically
acceptable salt thereof.
3. A compound of claim 1 wherein R.sup.1 and R.sup.2 together with
the two oxygen atoms to which they are attached form the ring
structure: ##STR00065## or a pharmaceutically acceptable salt
thereof.
4. A compound of claim 1 of formula II: ##STR00066## or a
pharmaceutically acceptable salt thereof, providing that the
compounds of the following formula are excluded: ##STR00067##
wherein R.sup.3 is aryl or an optionally substituted heteroaryl,
R.sup.4 is C.sub.1-10alkyl, R.sup.x is C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, arylC.sub.1-10alkyl or aryl, and W is O or
S.
5. A compound of claim 1 of formula IV: ##STR00068## or a
pharmaceutically acceptable salt thereof.
6. A compound of any previous claim wherein W is O.
7. A compound selected from the following: ##STR00069##
##STR00070## and pharmaceutically acceptable salts thereof
8. A pharmaceutical composition comprising a compound of any
previous claim or a pharmaceutically acceptable salt thereof
together with a pharmaceutically acceptable carrier or diluent.
9. A compound of any one of claims 1 to 7, or a pharmaceutical salt
thereof for use in therapy.
10. A compound of any one of claims 1 to 7, or a pharmaceutical
salt thereof for use in the treatment or prevention of cancer.
11. A method for the treatment of a cancer comprising administering
an effective treatment amount of a compound of any of claims 1-7,
or a pharmaceutically acceptable salt thereof or a composition of
claim 8.
12. The method of claim 7, wherein said compound or composition is
administered in combination with one or more other therapeutic
agent.
13. A combination comprising a compound of any one of claims 1-7,
or a pharmaceutically acceptable salt thereof and one, two, three
or more other therapeutic agents.
Description
FIELD
[0001] Provided herein are nucleoside derivatives, pharmaceutical
compositions comprising the compounds, processes of preparation
thereof, and methods of use thereof for treating cancer.
[0002] In certain embodiments, nucleoside and nucleotide compounds
and prodrugs are provided which can display remarkable efficacy and
bioavailability for the treatment of, for example, liver cancers in
a human. Liver cancers which can be treated include primary and
secondary liver cancers. In particular embodiments, the liver
cancer is hepatocellular carcinoma, cholangiocarcinoma, or biliary
tract cancer. In particular embodiments, the liver cancer is a
metastasis in the liver originated from other cancers (such as
colon cancer, pancreatic cancer, etc.). In certain embodiments, the
compounds described herein can be used to treat cancers such as
breast cancer, ovarian cancer, lung cancer, pancreatic cancer and
leukemic cancer.
BACKGROUND
[0003] Cancer is a disease characterized primarily by an
uncontrolled division of abnormal cells derived from a given normal
tissue and the invasion of adjacent tissues by these malignant
cells. Blood or lymphatic transportation can spread cancer cells to
other parts of the body leading to regional lymph nodes and to
distant sites (metastasis). Cancer is a complex, multistep process
that begins with minor preneoplastic changes, which may under
certain conditions progress to neoplasia. There are more than 100
different types of cancer, which can be grouped into broader
categories. The main categories include: carcinoma, sarcoma,
leukemia, lymphoma and myeloma, and central nervous system cancers.
The incidence of cancer continues to climb as the general
population ages, as new cancers develop, and as susceptible
populations (e.g., people infected with AIDS or excessively exposed
to sunlight) grow. A tremendous demand therefore exists for new
methods and compositions that can be used to treat patients with
cancer.
[0004] Hematologic or hematopoietic malignancies are cancers of the
blood or bone marrow, including leukemia and lymphoma. Leukemia is
a type of cancer of the blood characterized by abnormal
accumulation of immature white blood cells. There are four types of
leukemia: acute lymphocytic leukemia (ALL), acute myelogenous
leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic
myelogenous leukemia (CML). Acute leukemia is a rapidly progressing
disease that results in the accumulation of immature, functionless
cells in the marrow and blood. The marrow often stops producing
enough normal red cells, white cells and platelets. On the other
hand, chronic leukemia progresses more slowly and allows greater
numbers of more mature, functional cells to be made.
[0005] Leukemia can affect people at any age. The cause of most
cases of leukemia is not known. Extraordinary doses of radiation
and certain cancer therapies are possible causes. About 90% of
leukemia are diagnosed in adults. Cases of Chronic leukemia account
for 4.5 percent more cases than acute leukemia. The most common
types of leukemia in adults are acute myelogenous leukemia (AML),
with estimated 14,590 new cases in 2013, and chronic lymphocytic
leukemia (CLL), with about 15,680 new cases in 2013. Chronic
myelogenous leukemia (CML) was estimated to affect about 5,920
persons in 2013 (data from the Leukemia and Lymphoma Society, Facts
2013, August 2013).
[0006] The dramatic improvement in blood cancer treatment in the
latter part of the 20.sup.th century is largely the result of
chemotherapy. In addition, there are more than 50 drugs
individually used to treat these disorders and a number of
potential new therapies are under investigation in clinical trials.
While current chemotherapy can result in complete remissions, the
long term disease-free survival rate for leukemia, in particular
AML, is low. For example, the overall relative survival rate for
AML was estimated to be about 59% from 2003 to 2009. Therefore,
there is a clear and unmet need for effective therapeutics for
treatment of blood cancers, including leukemia.
[0007] Primary liver cancer is one of the most common forms of
cancer in the world. Hepatocellular carcinoma, also known as
malignant hepatoma, is the most common form of primary liver
cancer, and develops within the hepatocyte. Hepatocellular
carcinoma occurs mostly in men and patients that suffer from
cirrhosis. It has been the third leading cause of cancer deaths
worldwide (Block T M et al., 2003, Oncogene 22:5093-5107). Many
patients with hepatocellular carcinoma remain asymptomatic until
the disease is in its advanced stages, resulting in ineffective
treatment and poor prognosis; the majority of unresectable
hepatocellular carcinoma patients die within one year.
[0008] Treatment options for hepatocellular carcinoma have been
limited, especially in the case of advanced or recurrent
hepatocellular carcinoma. Surgery and radiation therapy are options
for early stage liver cancer, but not very effective for advanced
or recurrent hepatocellular carcinoma. Systematic chemotherapies
have not been particularly effective, and there are a very limited
number of drugs available for use. The recently approved kinase
inhibitor sorafenib has been shown to be effective in treating
hepatocellular carcinoma. However, it can slow or stop advanced
liver cancer from progressing for only a few months longer than
without treatment.
[0009] New therapies for the treatment or prevention of cancer are
needed.
SUMMARY
[0010] Provided herein are compounds useful, for example, for the
treatment of cancer, for example liver cancer. The compounds are
nucleoside and nucleotide analogs linked to a prodrug moiety. In
certain embodiments the nucleoside and nucleotide analogs linked to
a prodrug moiety can display remarkable efficacy or
bioavailability, or both, for the treatment of cancer, for example,
liver cancer in a human. Liver cancers which can be treated include
primary and secondary liver cancers. In particular embodiments, the
liver cancer is hepatocellular carcinoma, cholangiocarcinoma, or
biliary tract cancer. In particular embodiments, the liver cancer
is a metastasis in the liver originated from other cancers (such as
colon cancer, pancreatic cancer, etc.). In certain embodiments, the
compounds described herein can be used to treat cancers such as
breast cancer, ovarian cancer, lung cancer, pancreatic cancer and
leukemic cancer.
[0011] In certain embodiments, the compounds provided herein are
useful in the prevention and treatment of cancer, for example liver
such as hepatocellular carcinoma, cholangiocarcinoma, or biliary
tract cancer. These compounds or formulations can also be used
prophylactically to prevent or retard the progression of clinical
illness in individuals who have symptoms of cancer, for example
liver such as hepatocellular carcinoma, cholangiocarcinoma, or
biliary tract cancer. In certain embodiments, the compounds or
formulations described herein can be used to treat cancers such as
breast cancer, ovarian cancer, lung cancer, pancreatic cancer and
leukemic cancer.
[0012] A method for the treatment of a cancer, for example liver
cancer such as hepatocellular carcinoma, cholangiocarcinoma, or
biliary tract cancer, or metastasis in the liver originated from
other cancers (such as colon cancer, pancreatic cancer, etc.), in a
subject, such as a human, is also provided that includes
administering an effective amount of a compound provided herein,
administered either alone or in combination or alternation with
another anti-cancer agent, optionally in a pharmaceutically
acceptable carrier. In certain embodiments, the cancer is selected
from breast cancer, ovarian cancer, lung cancer, pancreatic cancer
and leukemic cancer.
[0013] Provided herein are compounds according to Formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein:
[0014] one of R.sup.1 and R.sup.2 is hydrogen and the other is
##STR00002##
[0015] or R.sup.1 and R.sup.2 together with the two oxygen atoms to
which they are attached form the ring structure:
##STR00003##
[0016] R.sup.3 is hydrogen, C.sub.1-10alkyl, C.sub.2-11alkenyl,
C.sub.2-11alkynyl, C.sub.1-10alkoxycarbonylC.sub.1-10alkyl,
C.sub.1-10alkylcarbonylthioC.sub.1-10alkyl,
C.sub.1-10alkyldisulfideC.sub.1-6alkyl, aryl or
heteroarylC.sub.1-10alkyl, wherein alkyl is optionally substituted
by one, two or three substituents independently selected from
halogen and hydroxy, and heteroaryl is substituted by one or two
substituents selected from C.sub.1-10alkyl and nitro;
[0017] R.sup.4 is hydrogen or C.sub.1-10alkyl;
[0018] R.sup.5 is C.sub.1-10alkoxycarbonyl,
C.sub.3-10cycloalkoxycarbony,
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl,
C.sub.3-10cycloalkylcarbonyoxy, aryl, aryloxy, C.sub.1-10alkylaryl,
arylC.sub.1-10alkyl, arylC.sub.1-10alkoxycarbonyl, aryloxycarbonyl,
heteroaryl, heteroarylC.sub.1-10alkyl or
C.sub.1-10alkylheteroaryl;
[0019] R.sup.6 is
##STR00004##
and
[0020] W is O or S,
[0021] providing that the compounds of the following formula are
excluded:
##STR00005##
[0022] wherein R.sup.3' is aryl or an optionally substituted
heteroaryl, R.sup.4' is C.sub.1-10alkyl, R.sup.x is C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, arylC.sub.1-10alkyl or aryl, and W is O.
[0023] In an embodiment, the compounds of the following formula are
excluded:
##STR00006##
[0024] wherein R.sup.3 is aryl or an optionally substituted
heteroaryl, R.sup.4 is C.sub.1-10alkyl, R.sup.x is C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, arylC.sub.1-10alkyl or aryl, and W is O or
S.
[0025] In one aspect, the compounds provided herein are provided or
administered in combination with a second therapeutic agent, such
as one useful for the treatment or prevention of cancer. Exemplary
second therapeutic agents are provided in detail elsewhere
herein.
[0026] In another aspect, provided herein are pharmaceutical
compositions, single unit dosage forms, and kits suitable for use
in treating or preventing disorders such as cancer, for example
liver cancer which comprise a therapeutically or prophylactically
effective amount of a compound provided herein, e.g., of Formulas
I-VIII, and a therapeutically or prophylactically effective amount
of a second therapeutic agent such as one useful for the treatment
or prevention of cancer, for example liver cancer. In certain
embodiments, the cancer is selected from breast cancer, ovarian
cancer, lung cancer, pancreatic cancer and leukemic cancer.
[0027] In certain embodiments, a method of treatment of a liver
disorder is provided comprising administering to an individual in
need thereof a treatment effective amount of a compound described
herein.
[0028] Liver cancers which can be treated include primary and
secondary liver cancers. In particular embodiments, the liver
cancer is hepatocellular carcinoma, cholangiocarcinoma, or biliary
tract cancer.
DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0029] Provided herein are compounds, compositions, and methods
useful for treating cancer in a subject. Further provided are
dosage forms useful for such methods. In certain embodiments, the
cancer is selected from liver cancer, breast cancer, ovarian
cancer, lung cancer, pancreatic cancer and leukemic cancer.
[0030] Definitions
[0031] When referring to the compounds provided herein, the
following terms have the following meanings unless indicated
otherwise. Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as is commonly understood
by one of ordinary skill in the art. In the event that there is a
plurality of definitions for a term herein, those in this section
prevail unless stated otherwise.
[0032] The term "alkyl," as used herein, unless otherwise
specified, refers to a saturated straight or branched hydrocarbon.
In certain embodiments, the alkyl group is a primary, secondary, or
tertiary hydrocarbon. The alkyl group includes one to ten carbon
atoms, i.e., C.sub.1 to C.sub.10 alkyl. In an embodiment, alkyl
group includes one to six carbon atoms, i.e., C.sub.1 to C.sub.6
alkyl. In certain embodiments, the alkyl group is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl,
isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl,
2,2-dimethylbutyl, or 2,3-dimethylbutyl.
[0033] The term "cycloalkyl," as used herein, unless otherwise
specified, refers to a saturated cyclic hydrocarbon. In certain
embodiments, the cycloalkyl group may be a saturated, and/or
bridged, and/or non-bridged, and/or a fused bicyclic group. The
cycloalkyl group includes three to ten carbon atoms, i.e., C.sub.3
to C.sub.10 cycloalkyl. In some embodiments, the cycloalkyl has
from 3 to 15 (C.sub.3-15), from 3 to 10 (C.sub.3-10), or from 3 to
7 (C.sub.3-7) carbon atoms. In certain embodiments, the cycloalkyl
group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, decalinyl or adamantyl.
[0034] The term "alkenyl" refers to monovalent olefinically
unsaturated hydrocarbon groups, having two to 11 carbon atoms,
including from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms,
which can be straight-chained or branched and having at least 1,
including from 1 to 2, site of olefinic unsaturation. Exemplary
alkenyl groups include ethenyl (i.e., vinyl, or --CH.dbd.CH.sub.2),
n-propenyl (--CH.sub.2CH.dbd.CH.sub.2), isopropenyl
(--C(CH.sub.3).dbd.CH.sub.2), and the like.
[0035] The term "alkynyl" refers to acetylenically unsaturated
hydrocarbon groups, having two to 11 carbon atoms or from 2 to 6
carbon atoms which can be straight-chained or branched and having
at least 1 or from 1 to 2 sites of alkynyl unsaturation.
Non-limiting examples of alkynyl groups include acetylenic, ethynyl
(--C.ident.CH), propargyl (--CH.sub.2C.ident.CH), and the like.
[0036] The term "aryl," as used herein, and unless otherwise
specified, refers to a substituent derived from an aromatic ring.
In an embodiment, an aryl group is a C.sub.6-C.sub.12 aryl group.
In an embodiment, an aryl group is phenyl, biphenyl or naphthyl. In
an embodiment, aryl is phenyl.
[0037] "C.sub.1-10alkoxy" and "C.sub.1-10alkoxyl" refer to the
group --OR' where R' is alkyl as defined herein. The alkoxyl or
alkoxy group is --OR', wherein R' is alkyl, and wherein alkyl is
C.sub.1 to C.sub.10 alkyl. Alkoxy and alkoxyl groups include, by
way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy,
and the like.
[0038] "C.sub.3-10cycloalkoxy" and "C.sub.3-10cyclolkoxyl" refer to
the group --OR' where R' is cycloalkyl as defined herein. The
alkoxyl or alkoxy group is --OR', wherein R' is cycloalkyl, and
wherein cycloalkyl is C.sub.3 to C.sub.10 cycloalkyl.
[0039] "Alkylcarbonyloxy" refers to a radical --O--C(O)-alkyl,
wherein alkyl is as defined herein.
[0040] "Cycloalkylcarbonyloxy" refers to a radical
--O--C(O)-cycloalkyl, wherein cycloalkyl is as defined herein.
[0041] "Aryloxy" refers to a radical --O-aryl, wherein aryl is as
defined herein.
[0042] "Alkoxycarbonyl" refers to a radical --C(O)-alkoxy where
alkoxy is as defined herein.
[0043] "Cycloalkoxycarbony" refers to a radical --C(O)-cycloalkoxy
where cycloalkoxy is as defined herein.
[0044] "Alkoxyalkylcarbonyl" refers to a radical
--C(O)-alkyl-alkoxy where alkoxy and alkyl are as defined
herein.
[0045] "Arylalkoxycarbonyl" refers to a radical --C(O)-alkoxy-aryl
where alkoxy and aryl are as defined herein.
[0046] "Aryloxycarbonyl" refers to a radical --C(O)--O-aryl where
aryl is as defined herein.
[0047] "Alkoxycarbonylalkyl" refers to a radical -alkyl-C(O)-alkoxy
where alkoxy and alkyl are as defined herein.
[0048] "Alkoxycarbonylalkoxy" refers to a radical
-alkoxy-C(O)-alkoxy where alkoxy and alkyl are as defined
herein.
[0049] As used herein, "alkylcarbonyloxyalkyl" refers to a radical
-alkyl-O--C(O)-alkyl, where alkyl is as defined herein.
[0050] As used herein, "alkyldisulfidealkyl" refers to a radical
-alkyl-S--S-alkyl, where alkyl is as defined herein.
[0051] As used herein, "alkylcarbonylthioalkyl" refers to a radical
-alkyl-S--C(O)-alkyl, where alkyl is as defined herein.
[0052] "Alkylaryl" refers to an aryl group with an alkyl
substituent where alkyl and aryl are as defined herein.
[0053] "Arylalkyl" refers to an alkyl group with an aryl
substituent where alkyl and aryl are as defined herein.
[0054] "Oxo" refers to the group .dbd.O.
[0055] "Carboxyl" or "carboxy" refers to the radical --C(O)OH.
[0056] "Carbonyl" refers to the radical --C(O).
[0057] "Halogen" or "halo" refers to chloro, bromo, fluoro, or
iodo.
[0058] "Amino" refers to the group --NR.sup.1'R.sup.2' or
--NR.sup.1'--, wherein R.sup.1' and R.sup.2' are independently
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl,
or heteroaryl, each of which is as defined herein. In an embodiment
each of R.sup.1' and R.sup.2' is independently hydrogen or alkyl.
In an embodiment each of R.sup.1' and R.sup.2' is hydrogen.
[0059] The term "heteroaryl" refers to a monovalent monocyclic
aromatic group and/or multicyclic aromatic group that contain at
least one aromatic ring, wherein at least one aromatic ring
contains one or more heteroatoms independently selected from O, S
and N in the ring. Heteroaryl groups are bonded to the rest of the
molecule through the aromatic ring. Each ring of a heteroaryl group
can contain one or two O atoms, one or two S atoms, and/or one to
four N atoms, provided that the total number of heteroatoms in each
ring is four or less and each ring contains at least one carbon
atom. In certain embodiments, the heteroaryl has from 5 to 20, from
5 to 15, or from 5 to 10 ring atoms. In an embodiment, heteroaryl
has 5 ring atoms. Examples of monocyclic heteroaryl groups include,
but are not limited to, furanyl, imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl,
thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples
of bicyclic heteroaryl groups include, but are not limited to,
benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,
benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,
benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,
indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,
isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,
pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,
thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic
heteroaryl groups include, but are not limited to, acridinyl,
benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,
phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxazinyl and xanthenyl. In an embodiment,
heteroaryl is selected from imidazoly, thiazolyl, thienyl and
furyl. In an embodiment, heteroaryl is N-methylimidazolyl. In
certain embodiments, heteroaryl may also be optionally substituted
as described herein. In an embodiment heteroaryl is substituted
with one nitro group and one methyl group. In an embodiment
heteroaryl is substituted with one nitro group.
[0060] The term "heteroarylalkyl" refers to an alkyl group with a
heteroaryl substituent.
[0061] The term "alkylheteroaryl" refers to a heteroaryl group with
an alkyl substituent.
[0062] The term "protecting group" as used herein and unless
otherwise defined refers to a group that is added to an oxygen,
nitrogen or phosphorus atom to prevent its further reaction or for
other purposes. A wide variety of oxygen and nitrogen protecting
groups are known to those skilled in the art of organic
synthesis.
[0063] "Pharmaceutically acceptable salt" refers to any salt of a
compound provided herein which retains its biological properties
and which is not toxic or otherwise undesirable for pharmaceutical
use. Such salts may be derived from a variety of organic and
inorganic counter-ions well known in the art. Such salts include,
but are not limited to: (1) acid addition salts formed with organic
or inorganic acids such as hydrochloric, hydrobromic, sulfuric,
nitric, phosphoric, sulfamic, acetic, trifluoroacetic,
trichloroacetic, propionic, hexanoic, cyclopentylpropionic,
glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic,
ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic,
3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic,
lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic,
2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic,
2-naphthalenesulfonic, 4-toluenesulfonic, camphoric,
camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic,
glucoheptonic, 3-phenylpropionic, trimethylacetic,
tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic,
hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic,
muconic acid and the like acids; or (2) base addition salts formed
when an acidic proton present in the parent compound either (a) is
replaced by a metal ion, e.g., an alkali metal ion, an alkaline
earth ion or an aluminum ion, or alkali metal or alkaline earth
metal hydroxides, such as sodium, potassium, calcium, magnesium,
aluminum, lithium, zinc, and barium hydroxide, ammonia or (b)
coordinates with an organic base, such as aliphatic, alicyclic, or
aromatic organic amines, such as ammonia, methylamine,
dimethylamine, diethylamine, picoline, ethanolamine,
diethanolamine, triethanolamine, ethylenediamine, lysine, arginine,
ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine
piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium
hydroxide, and the like.
[0064] Pharmaceutically acceptable salts further include, by way of
example only and without limitation, sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium and the like, and when the
compound contains a basic functionality, salts of non-toxic organic
or inorganic acids, such as hydrohalides, e.g. hydrochloride and
hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate,
trifluoroacetate, trichloroacetate, propionate, hexanoate,
cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate,
malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate,
tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate,
picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate
(mesylate), ethanesulfonate, 1,2-ethane-disulfonate,
2-hydroxyethanesulfonate, benzenesulfonate (besylate),
4-chlorobenzenesulfonate, 2-naphthalenesulfonate,
4-toluenesulfonate, camphorate, camphorsulfonate,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate,
3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl
sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate,
salicylate, stearate, cyclohexylsulfamate, quinate, muconate and
the like.
[0065] Unless expressly stated to the contrary, substitution by a
named substituent is permitted on any atom in a chain or ring
provided such substitution is chemically allowed and results in a
stable compound. A "stable" compound is a compound which can be
prepared and isolated and whose structure and properties remain or
can be caused to remain essentially unchanged for a period of time
sufficient to allow use of the compound for the purposes described
herein (e.g., therapeutic or prophylactic administration to a
subject).
[0066] To the extent substituents and substituent patterns provide
for the existence of tautomers (e.g., keto-enol tautomers) in the
compounds described herein, all tautomeric forms of these
compounds, whether present individually or in mixtures, are within
the scope of the present disclosure. Compounds of the present
disclosure having a hydroxy substituent on a carbon atom of a
heteroaromatic ring are understood to include compounds in which
only the hydroxy is present, compounds in which only the tautomeric
keto form (i.e., an oxo substituent) is present, and compounds in
which the keto and enol forms are both present.
[0067] As used herein when referring to a substituent on a sugar
ring of a nucleoside, the term "beta" refers to a substituent on
the same side of the plane of the sugar ring as the 5' carbon and
the term "alpha" refers to a substituent on the opposite side of
the plane of the sugar ring from the 5' carbon. As shown below,
substituent "A" is in the "alpha" position, and substituent "B" is
in the "beta" position with respect to the 5' carbon:
##STR00007##
[0068] The term "substantially free of" or "substantially in the
absence of," when used in connection with an article (including,
but not limited to, a compound, a salt thereof, a solvate thereof,
a solid form thereof, and the like), refers to the article that
includes at least 85% or 90% by weight, in certain embodiments,
95%, 98%, 99%, or 100% by weight, of the designated article. For
example, the term "substantially free of" or "substantially in the
absence of" with respect to a nucleoside composition can refer to a
nucleoside composition that includes at least 85% or 90% by weight,
in certain embodiments, 95%, 98%, 99%, or 100% by weight, of the
designated stereoisomer of that nucleoside. In certain embodiments,
in the methods and compounds provided herein, the compounds are
substantially free of undesignated stereoisomers or other
compounds. For another example, the term "substantially free of" or
"substantially in the absence of" with respect to a solid form can
refer to a solid form that includes at least 85% or 90% by weight,
in certain embodiments, 95%, 98%, 99%, or 100% by weight, of the
designated solid form. In certain embodiments, in the methods and
compounds provided herein, the solid form is substantially free of
other solid forms.
[0069] Similarly, the term "isolated" with respect to a nucleoside
composition refers to a nucleoside composition that includes at
least 85%, 90%, 95%, 98%, or 99% to 100% by weight, of the
nucleoside, the remainder comprising other chemical species or
stereoisomers. Similarly, the term "isolated" with respect to a
solid form of a compound refers to a solid that includes at least
85%, 90%, 95%, 98%, or 99% to 100% by weight, of such solid form of
the compound, the remainder comprising other solid forms of the
compound, other compounds, solvents, and/or other impurities.
[0070] "Solvate" refers to a compound provided herein or a salt
thereof, that further includes a stoichiometric or
non-stoichiometric amount of solvent bound by non-covalent
intermolecular forces. Where the solvent is water, the solvate is a
hydrate.
[0071] "Isotopic composition" refers to the amount of each isotope
present for a given atom, and "natural isotopic composition" refers
to the naturally occurring isotopic composition or abundance for a
given atom. Atoms containing their natural isotopic composition may
also be referred to herein as "non-enriched" atoms. Unless
otherwise designated, the atoms of the compounds recited herein are
meant to represent any stable isotope of that atom. For example,
unless otherwise stated, when a position is designated specifically
as "H" or "hydrogen," the position is understood to have hydrogen
at its natural isotopic composition.
[0072] "Isotopic enrichment" refers to the percentage of
incorporation of an amount of a specific isotope at a given atom in
a molecule in the place of that atom's natural isotopic abundance.
For example, deuterium enrichment of 1% at a given position means
that 1% of the molecules in a given sample contain deuterium at the
specified position. Because the naturally occurring distribution of
deuterium is about 0.0156%, deuterium enrichment at any position in
a compound synthesized using non-enriched starting materials is
about 0.0156%. The isotopic enrichment of the compounds provided
herein can be determined using conventional analytical methods
known to one of ordinary skill in the art, including mass
spectrometry and nuclear magnetic resonance spectroscopy.
[0073] "Isotopically enriched" refers to an atom having an isotopic
composition other than the natural isotopic composition of that
atom. "Isotopically enriched" may also refer to a compound
containing at least one atom having an isotopic composition other
than the natural isotopic composition of that atom.
[0074] As used herein, "alkyl," "alkenyl," "alkynyl," "cycloalkyl,"
"aryl," "alkoxy," "alkylcarbonyloxy," "aryloxy," "alkoxycarbonyl,"
"alkoxyalkylcarbonyl," "arylalkoxycarbonyl, "aryloxycarbonyl,"
"alkoxycarbonylalkyl," "alkoxycarbonylalkoxy,"
"alkylcarbonyloxyalkyl" "alkyldisulfidealkyl,"
"alkylcarbonylthioalkyl" "arylalkyl," "alkylaryl," "carboxyl,"
"carbonyl," "heteroaryl," "heteroarylalkyl," "alkylheteroaryl," and
"amino acid" groups optionally comprise deuterium at one or more
positions where hydrogen atoms are present, and wherein the
deuterium composition of the atom or atoms is other than the
natural isotopic composition.
[0075] As used herein, "alkyl," "alkenyl," "alkynyl," "cycloalkyl,"
"aryl," "alkoxy," "alkylcarbonyloxy," "aryloxy," "alkoxycarbonyl,"
"alkoxyalkylcarbonyl," "arylalkoxycarbonyl, "aryloxycarbonyl,"
"alkoxycarbonylalkyl," "alkoxycarbonylalkoxy,"
"alkylcarbonyloxyalkyl" "alkyldisulfidealkyl"
"alkylcarbonylthioalkyl" "arylalkyl," "alkylaryl," "carboxyl,"
"carbonyl," "heteroaryl," "heteroarylalkyl," "alkylheteroaryl," and
"amino acid" groups optionally comprise carbon-13 at an amount
other than the natural isotopic composition.
[0076] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
[0077] As used herein, the term "Emax" refers to an amount,
concentration or dosage of a particular test compound that achieves
a 100% inhibition of a maximal response in an assay that measures
such response.
[0078] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response in an assay that measures
such response.
[0079] The term "host," as used herein, refers to any unicellular
or multicellular organism, including cell lines and animals, and in
certain embodiments, a human. Alternatively, the host can be
carrying a part of the Flaviviridae viral genome, whose replication
or function can be altered by the compounds of the present
invention. The term host specifically includes infected cells,
cells transfected with all or part of the Flaviviridae genome and
animals, in particular, primates (including chimpanzees) and
humans. In most animal applications of the present invention, the
host is a human patient. Veterinary applications, in certain
indications, however, are clearly anticipated by the present
invention (such as chimpanzees).
[0080] As used herein, the terms "subject" and "patient" are used
interchangeably herein. The terms "subject" and "subjects" refer to
an animal, such as a mammal including a non-primate (e.g., a cow,
pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey
such as a cynomolgous monkey, a chimpanzee and a human), and for
example, a human. In another embodiment, the subject is a farm
animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or
a cat). In certain embodiments, the subject is a human.
[0081] As used herein, the terms "therapeutic agent" and
"therapeutic agents" refer to any agent(s) which can be used in the
treatment or prevention of a disorder or one or more symptoms
thereof. In certain embodiments, the term "therapeutic agent"
includes a compound provided herein. In certain embodiments, a
therapeutic agent is an agent which is known to be useful for, or
has been or is currently being used for the treatment or prevention
of a disorder or one or more symptoms thereof.
[0082] "Therapeutically effective amount" refers to an amount of a
compound or composition that, when administered to a subject for
treating a disease, is sufficient to effect such treatment for the
disease. A "therapeutically effective amount" can vary depending
on, inter alia, the compound, the disease and its severity, and the
age, weight, etc., of the subject to be treated.
[0083] "Treating" or "treatment" of any disease or disorder refers,
in certain embodiments, to ameliorating a disease or disorder that
exists in a subject. In another embodiment, "treating" or
"treatment" includes ameliorating at least one physical parameter,
which may be indiscernible by the subject. In yet another
embodiment, "treating" or "treatment" includes modulating the
disease or disorder, either physically (e.g., stabilization of a
discernible symptom) or physiologically (e.g., stabilization of a
physical parameter) or both. In yet another embodiment, "treating"
or "treatment" includes delaying the onset of the disease or
disorder.
[0084] As used herein, the terms "prophylactic agent" and
"prophylactic agents" as used refer to any agent(s) which can be
used in the prevention of a disorder or one or more symptoms
thereof. In certain embodiments, the term "prophylactic agent"
includes a compound provided herein. In certain other embodiments,
the term "prophylactic agent" does not refer a compound provided
herein. For example, a prophylactic agent is an agent which is
known to be useful for, or has been or is currently being used to
prevent or impede the onset, development, progression and/or
severity of a disorder.
[0085] As used herein, the phrase "prophylactically effective
amount" refers to the amount of a therapy (e.g., prophylactic
agent) which is sufficient to result in the prevention or reduction
of the development, recurrence or onset of one or more symptoms
associated with a disorder, or to enhance or improve the
prophylactic effect(s) of another therapy (e.g., another
prophylactic agent).
[0086] Compounds
[0087] Provided herein are nucleoside compounds useful for the
treatment of cancers, for example liver cancers such as
hepatocellular carcinoma, cholangiocarcinoma, or biliary tract
cancer. The nucleoside compounds can be formed as described herein
and used for the treatment of cancers, for example liver cancers
such as hepatocellular carcinoma, cholangiocarcinoma, or biliary
tract cancer. In certain embodiments, the cancer is selected from
breast cancer, ovarian cancer, lung cancer, pancreatic cancer and
leukemic cancer.
[0088] The compounds described herein may optionally be used in the
form of a pharmaceutically acceptable salt. It is understood that
references to compounds or pharmaceutically salts thereof would
include compounds in present form as well as in different forms,
such as polymorphs and solvates (including hydrates), as
applicable.
[0089] Formula I includes a chiral amino acid residue linked to a
5'-phosphoramidate group. Those of skill in the art will recognize
that the amino acid residue has R stereochemistry at the carbon
bonded to R.sup.4; i.e., that it is a D-amino acid residue.
[0090] Some compounds provided herein are based, at least in part,
on the discovery that D-amino acid phosphoramidate prodrugs can
provide superior human pharmacokinetics including superior
accumulation of active nucleoside and nucleotide analogs in target
cells, such as liver cells. In certain embodiments, the compounds
provided herein are D-amino acid, R.sub.P phosphoramidate
compounds. In certain embodiments, the compounds provided herein
are D-amino acid, S.sub.P phosphoramidate compounds. Any compound
provided herein is preferably in the form of a composition that is
substantially free of other stereoisomers of the compound, as
described herein.
[0091] In an embodiment, the compounds described herein are
prodrugs of the compound thiarabine, of the following
structure:
##STR00008##
[0092] In one embodiment one of R.sup.1 and R.sup.2 is hydrogen and
the other is
##STR00009##
[0093] In one embodiment R.sup.1 and R.sup.2 together with the two
oxygen atoms to which they are attached form the ring
structure:
##STR00010##
[0094] In one embodiment is a compound of formula II:
##STR00011##
providing that the compounds of the following formula are
excluded:
##STR00012##
[0095] wherein R.sup.3 is aryl or an optionally substituted
heteroaryl, R.sup.4 is C.sub.1-10alkyl, R.sup.x is C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, arylC.sub.1-10alkyl or aryl, and W is O or
S.
[0096] In one embodiment is a compound of formula III:
##STR00013##
[0097] In one embodiment is a compound of formula IV:
##STR00014##
[0098] In one embodiment is a compound of formula V:
##STR00015##
[0099] In one embodiment, one of R.sup.1 and R.sup.2 is hydrogen
and the other is
##STR00016##
or
[0100] R.sup.1 and R.sup.2 together with the two oxygen atoms to
which they are attached form the ring structure:
##STR00017##
[0101] In one embodiment, one of R.sup.1 and R.sup.2 is hydrogen
and the other is
##STR00018##
or
[0102] R.sup.1 and R.sup.2 together with the two oxygen atoms to
which they are attached form the ring structure:
##STR00019##
[0103] In one embodiment R.sup.2 is hydrogen and R.sup.1 is
##STR00020##
[0104] In one embodiment R.sup.1 is hydrogen and R.sup.2 is
##STR00021##
[0105] In one embodiment R.sup.1 and R.sup.2 together with the two
oxygen atoms to which they are attached form the ring
structure.
##STR00022##
[0106] In one embodiment, R.sup.4 is hydrogen or C.sub.1-10alkyl,
and R.sup.5 is C.sub.1-10alkoxycarbonyl or aryl.
[0107] In one embodiment, R.sup.4 is C.sub.1-10alkyl, and R.sup.5
is C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl.
[0108] In one embodiment, R.sup.4 is hydrogen, and R.sup.5 is
aryl.
[0109] In one embodiment, R.sup.4 is hydrogen, methyl or
2-methylpropyl.
[0110] In one embodiment, R.sup.5 is C.sub.1-10alkoxycarbonyl,
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl or aryl.
[0111] In one embodiment, R.sup.5 is
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl or aryl.
[0112] In one embodiment, R.sup.5 is
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl,
C.sub.3-10cycloalkylcarbonyoxy, aryl, aryloxy, C.sub.1-10alkylaryl,
arylC.sub.1-10alkyl, heteroaryl or heteroarylC.sub.1-10alkyl.
[0113] In one embodiment, R.sup.5 is methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, methylcarbonyloxymethyl or
phenyl.
[0114] In one embodiment, R.sup.5 is methylcarbonyloxymethyl or
phenyl.
[0115] In one embodiment, R.sup.5 is phenoxycarbonyl,
benzoxycarbonyl and cyclopentyl.
[0116] In one embodiment, R.sup.3 is hydrogen,
C.sub.1-10alkoxycarbonylC.sub.1-10alkyl,
C.sub.1-10alkyldisulfideC.sub.1-6alkyl, aryl or
heteroarylC.sub.1-10alkyl, wherein heteroaryl is substituted by one
or two substituents selected from C.sub.1-10alkyl and nitro.
[0117] In one embodiment, R.sup.3 is
C.sub.1-10alkoxycarbonylC.sub.1-10alkyl,
C.sub.1-10alkyldisulfideC.sub.1-6alkyl, aryl or
heteroarylC.sub.1-10alkyl, wherein heteroaryl is substituted by one
or two substituents selected from C.sub.1-10alkyl and nitro.
[0118] In one embodiment, R.sup.3 is not aryl.
[0119] In one embodiment, R.sup.3 is hydrogen,
methoxycarbonylmethyl, ethoxycarbonylmethyl,
(tertbutyldisulfanyl)ethyl, phenyl, (nitrofuryl)methyl or
(methylnitroimadazolyl)methyl.
[0120] In one embodiment, R.sup.3 is hydrogen,
methoxycarbonylmethyl, ethoxycarbonylmethyl,
2-(tertbutyldisulfanyl)ethyl, phenyl, (5-nitro-2-furyl)methyl or
(3-methyl-2-nitroimadazol-4-yl)methyl.
[0121] In one embodiment, R.sup.3 is heteroarylC.sub.1-6alkyl,
which is optionally substituted by one nitro group.
[0122] In an embodiment W is O. In another embodiment W is S.
[0123] In one embodiment is a compound of formula VI:
##STR00023##
[0124] wherein R.sup.5 is
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl,
C.sub.3-10cycloalkylcarbonyoxy, aryl, aryloxy, C.sub.1-10alkylaryl,
arylC.sub.1-10alkyl, heteroaryl or heteroarylC.sub.1-10alkyl.
[0125] In one embodiment is a compound of formula VII:
##STR00024##
[0126] wherein R.sup.5 is C.sub.1-10alkoxycarbonyl,
C.sub.3-10cycloalkoxycarbony,
C.sub.1-10alkylcarbonyloxyC.sub.1-10alkyl,
C.sub.3-10cycloalkylcarbonyoxy, aryl, aryloxy, C.sub.1-10alkylaryl,
arylC.sub.1-10alkyl, arylC.sub.1-10alkoxycarbonyl, aryloxycarbonyl,
heteroaryl or heteroarylC.sub.1-10alkyl.
[0127] In one embodiment is a compound of formula VIII:
[0128] wherein R is C.sub.1-10alkyl.
##STR00025##
[0129] In an embodiment, R is isopropyl.
[0130] In an embodiment:
[0131] R.sup.1 is
##STR00026##
[0132] R.sup.2 is hydrogen,
[0133] R.sup.3 is heteroarylC.sub.1-10alkyl;
[0134] R.sup.4 is hydrogen;
[0135] R.sup.5 is aryl; and
[0136] W is O.
[0137] All other variables in each one of the above embodiments are
as defined in each of formulae I, II, III, IV, V, VI, VII and VIII
and in other embodiments.
[0138] In certain embodiments, provided herein are compounds
according to any of the following formulae:
##STR00027## ##STR00028## ##STR00029##
and pharmaceutically acceptable salt thereof.
[0139] Particular compounds are:
##STR00030## ##STR00031##
and pharmaceutically acceptable salt thereof.
[0140] In some embodiments, provided herein are: [0141] (a)
compounds as described herein, e.g., of Formulas I-VIII, or
pharmaceutically acceptable salts and compositions thereof; [0142]
(b) compounds as described herein, e.g., of Formulas I-VIII, or
pharmaceutically acceptable salts and compositions thereof for use
in therapy; [0143] (c) compounds as described herein, e.g., of
Formulas I-VIII, or pharmaceutically acceptable salts and
compositions thereof for use in the treatment and/or prophylaxis of
a cancer, for example liver cancer, breast cancer, ovarian cancer,
lung cancer, pancreatic cancer or leukemic cancer; [0144] (d)
processes for the preparation of compounds as described herein,
e.g., of Formulas I-VIII, as described in more detail elsewhere
herein; [0145] (e) pharmaceutical compositions comprising a
compound as described herein, e.g., of Formulas I-VIII, or a
pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier or diluent; [0146] (f)
pharmaceutical formulations comprising a compound as described
herein, e.g., of Formulas I-VIII, or a pharmaceutically acceptable
salt thereof together with one or more other effective therapeutic
agents, e.g. anti-cancer agents, optionally in a pharmaceutically
acceptable carrier or diluent; [0147] (g) a method for the
treatment and/or prophylaxis of a host with cancer, for example
liver cancer, breast cancer, ovarian cancer, lung cancer,
pancreatic cancer or leukemic cancer that includes the
administration of an effective amount of a compound as described
herein, e.g., of Formulas I-VIII, its pharmaceutically acceptable
salt or composition; [0148] (h) a method for the treatment and/or
prophylaxis of a host with cancer, for example liver cancer, breast
cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemic
cancer that includes the administration of an effective amount of a
compounds as described herein, e.g., of Formulas I-VIII, its
pharmaceutically acceptable salt or composition in combination
and/or alternation with one or more other effective therapeutic
agent, e.g. anti-cancer agent; or [0149] (i) combinations
comprising compounds as described herein, e.g., of Formulas I-VIII,
or pharmaceutically acceptable salts, and one, two, three or more
other therapeutic agents, e.g. anti-cancer agents.
[0150] Optically Active Compounds
[0151] It is appreciated that compounds provided herein have
several chiral centers and may exist in and be isolated in
optically active and racemic forms. Some compounds may exhibit
polymorphism. It is to be understood that any racemic,
optically-active, diastereomeric, polymorphic, or stereoisomeric
form, or mixtures thereof, of a compound provided herein, which
possess the useful properties described herein is within the scope
of the invention. It being well known in the art how to prepare
optically active forms (for example, by resolution of the racemic
form by recrystallization techniques, by synthesis from
optically-active starting materials, by chiral synthesis, or by
chromatographic separation using a chiral stationary phase).
[0152] The compounds described herein, i.e. compounds of any of
Formulas I-VIII, may have one or more chiral (asymmetric) centers.
The present disclosure encompasses all stereoisomeric forms of the
compounds described herein. Centers of asymmetry that are present
in the compounds described herein, can all independently of one
another have (R) or (S) configuration. When bonds to a chiral atom,
such as carbon or phosphorus, are depicted as straight lines in the
structural formulas of the compounds described herein, or when a
compound name is recited without an (R) or (S) chiral designation
for a chiral atom, it is understood that both the (R) and (S)
configurations of each such chiral atoms, and hence each enantiomer
or diastereomer and mixtures thereof, are embraced within the
structural formula or by the name. The production of specific
stereoisomers or mixtures thereof may be identified in the Examples
where such stereoisomers or mixtures were obtained, but this in no
way limits the inclusion of all stereoisomers and mixtures thereof
from being within the scope of the present disclosure.
[0153] Since the 1' and 4' carbons of a nucleoside are chiral,
their non-hydrogen substituents (the base and the CHOR groups,
respectively) can be either cis (on the same side) or trans (on
opposite sides) with respect to the sugar ring system. The four
optical isomers therefore are represented by the following
configurations (when orienting the sugar moiety in a horizontal
plane such that the oxygen atom is in the back): cis (with both
groups "up", which corresponds to the configuration of naturally
occurring .beta.-D nucleosides), cis (with both groups "down",
which is a non-naturally occurring .beta.-L configuration), trans
(with the C2' substituent "up" and the C4' substituent "down"), and
trans (with the C2' substituent "down" and the C4' substituent
"up"). The "D-nucleosides" are cis nucleosides in a natural
configuration and the "L-nucleosides" are cis nucleosides in the
non-naturally occurring configuration.
[0154] Likewise, most amino acids are chiral (designated as L or D,
wherein the L enantiomer is the naturally occurring configuration)
and can exist as separate enantiomers.
[0155] Examples of methods to obtain optically active materials are
known in the art, and include at least the following. [0156] i)
physical separation of crystals--a technique whereby macroscopic
crystals of the individual enantiomers are manually separated. This
technique can be used if crystals of the separate enantiomers
exist, i.e., the material is a conglomerate, and the crystals are
visually distinct; [0157] ii) simultaneous crystallization--a
technique whereby the individual enantiomers are separately
crystallized from a solution of the racemate, possible only if the
latter is a conglomerate in the solid state; [0158] iii) enzymatic
resolutions--a technique whereby partial or complete separation of
a racemate by virtue of differing rates of reaction for the
enantiomers with an enzyme; [0159] iv) enzymatic asymmetric
synthesis--a synthetic technique whereby at least one step of the
synthesis uses an enzymatic reaction to obtain an enantiomerically
pure or enriched synthetic precursor of the desired enantiomer;
[0160] v) chemical asymmetric synthesis--a synthetic technique
whereby the desired enantiomer is synthesized from an achiral
precursor under conditions that produce asymmetry (i.e., chirality)
in the product, which may be achieved using chiral catalysts or
chiral auxiliaries; [0161] vi) diastereomer separations--a
technique whereby a racemic compound is reacted with an
enantiomerically pure reagent (the chiral auxiliary) that converts
the individual enantiomers to diastereomers. The resulting
diastereomers are then separated by chromatography or
crystallization by virtue of their now more distinct structural
differences and the chiral auxiliary later removed to obtain the
desired enantiomer; [0162] vii) first- and second-order asymmetric
transformations--a technique whereby diastereomers from the
racemate equilibrate to yield a preponderance in solution of the
diastereomer from the desired enantiomer or where preferential
crystallization of the diastereomer from the desired enantiomer
perturbs the equilibrium such that eventually in principle all the
material is converted to the crystalline diastereomer from the
desired enantiomer. The desired enantiomer is then released from
the diastereomer; [0163] viii) kinetic resolutions--this technique
refers to the achievement of partial or complete resolution of a
racemate (or of a further resolution of a partially resolved
compound) by virtue of unequal reaction rates of the enantiomers
with a chiral, non-racemic reagent or catalyst under kinetic
conditions; [0164] ix) enantiospecific synthesis from non-racemic
precursors--a synthetic technique whereby the desired enantiomer is
obtained from non-chiral starting materials and where the
stereochemical integrity is not or is only minimally compromised
over the course of the synthesis; [0165] x) chiral liquid
chromatography--a technique whereby the enantiomers of a racemate
are separated in a liquid mobile phase by virtue of their differing
interactions with a stationary phase. The stationary phase can be
made of chiral material or the mobile phase can contain an
additional chiral material to provoke the differing interactions;
[0166] xi) chiral gas chromatography--a technique whereby the
racemate is volatilized and enantiomers are separated by virtue of
their differing interactions in the gaseous mobile phase with a
column containing a fixed non-racemic chiral adsorbent phase;
[0167] xii) extraction with chiral solvents--a technique whereby
the enantiomers are separated by virtue of preferential dissolution
of one enantiomer into a particular chiral solvent; [0168] a)
transport across chiral membranes--a technique whereby a racemate
is placed in contact with a thin membrane barrier. The barrier
typically separates two miscible fluids, one containing the
racemate, and a driving force such as concentration or pressure
differential causes preferential transport across the membrane
barrier. Separation occurs as a result of the non-racemic chiral
nature of the membrane which allows only one enantiomer of the
racemate to pass through.
[0169] In some embodiments, provided is a composition that
comprises a substantially pure designated enantiomer of a compound
described herein. In certain embodiments, in the methods and
compounds of this invention, the compounds are substantially free
of other enantiomers. In some embodiments, a composition includes a
compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by
weight, of the compound, the remainder comprising other chemical
species or enantiomers.
[0170] In an embodiment, enantiomers are a subject of the invention
in enantiomerically pure form, both as levorotatory and as
dextrorotatory antipodes, in the form of racemates and in the form
of mixtures of the two enantiomers in all ratios. In the case of a
cis/trans isomerism the invention includes both the cis form and
the trans form as well as mixtures of these forms in all ratios.
The preparation of individual stereoisomers can be carried out, if
desired, by separation of a mixture by customary methods, for
example by chromatography or crystallization, by the use of
stereochemically uniform starting materials for the synthesis or by
stereoselective synthesis. Optionally a derivatization can be
carried out before a separation of stereoisomers. The separation of
a mixture of stereoisomers can be carried out at an intermediate
step during the synthesis of a compound described herein, e.g., a
compound of any of Formulas I-VIII, or it can be done on a final
racemic product. Absolute stereochemistry may be determined by
X-ray crystallography of crystalline products or crystalline
intermediates which are derivatized, if necessary, with a reagent
containing a stereogenic center of known configuration.
Alternatively, absolute stereochemistry may be determined by
Vibrational Circular Dichroism (VCD) spectroscopic analysis. The
present invention includes all such isomers, as well as salts,
solvates (which includes hydrates) and solvated salts of such
racemates, enantiomers, diastereomers and tautomers and mixtures
thereof.
[0171] Isotopically Enriched Compounds
[0172] Also provided herein are isotopically enriched compounds,
including but not limited to isotopically enriched 5'-D-amino acid
phosphoramidate compounds.
[0173] Isotopic enrichment (for example, deuteration) of
pharmaceuticals to improve pharmacokinetics ("PK"),
pharmacodynamics ("PD"), and toxicity profiles, has been
demonstrated previously with some classes of drugs. See, for
example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982);
Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold
et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab.
Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994);
Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol.
Interact. 117: 191 (1999).
[0174] Isotopic enrichment of a drug can be used, for example, to
(1) reduce or eliminate unwanted metabolites, (2) increase the
half-life of the parent drug, (3) decrease the number of doses
needed to achieve a desired effect, (4) decrease the amount of a
dose necessary to achieve a desired effect, (5) increase the
formation of active metabolites, if any are formed, and/or (6)
decrees the production of deleterious metabolites in specific
tissues and/or create a more effective drug and/or a safer drug for
combination therapy, whether the combination therapy is intentional
or not.
[0175] Replacement of an atom for one of its isotopes often will
result in a change in the reaction rate of a chemical reaction.
This phenomenon is known as the Kinetic Isotope Effect ("KIE"). For
example, if a C--H bond is broken during a rate-determining step in
a chemical reaction (i.e. the step with the highest transition
state energy), substitution of a deuterium for that hydrogen will
cause a decrease in the reaction rate and the process will slow
down. This phenomenon is known as the Deuterium Kinetic Isotope
Effect ("DKIE"). (See, e.g., Foster et al., Adv. Drug Res., vol.
14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol.,
vol. 77, pp. 79-88 (1999)).
[0176] The magnitude of the DKIE can be expressed as the ratio
between the rates of a given reaction in which a C--H bond is
broken, and the same reaction where deuterium is substituted for
hydrogen. The DKIE can range from about 1 (no isotope effect) to
very large numbers, such as 50 or more, meaning that the reaction
can be fifty, or more, times slower when deuterium is substituted
for hydrogen. High DKIE values may be due in part to a phenomenon
known as tunneling, which is a consequence of the uncertainty
principle. Tunneling is ascribed to the small mass of a hydrogen
atom, and occurs because transition states involving a proton can
sometimes form in the absence of the required activation energy.
Because deuterium has more mass than hydrogen, it statistically has
a much lower probability of undergoing this phenomenon.
[0177] Tritium ("T") is a radioactive isotope of hydrogen, used in
research, fusion reactors, neutron generators and
radiopharmaceuticals. Tritium is a hydrogen atom that has 2
neutrons in the nucleus and has an atomic weight close to 3. It
occurs naturally in the environment in very low concentrations,
most commonly found as T.sub.2O. Tritium decays slowly
(half-life=12.3 years) and emits a low energy beta particle that
cannot penetrate the outer layer of human skin. Internal exposure
is the main hazard associated with this isotope, yet it must be
ingested in large amounts to pose a significant health risk. As
compared with deuterium, a lesser amount of tritium must be
consumed before it reaches a hazardous level. Substitution of
tritium ("T") for hydrogen results in yet a stronger bond than
deuterium and gives numerically larger isotope effects. Similarly,
substitution of isotopes for other elements, including, but not
limited to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen, may lead to a similar kinetic isotope
effect.
[0178] For example, the DKIE was used to decrease the
hepatotoxicity of halothane by presumably limiting the production
of reactive species such as trifluoroacetyl chloride. However, this
method may not be applicable to all drug classes. For example,
deuterium incorporation can lead to metabolic switching. The
concept of metabolic switching asserts that xenogens, when
sequestered by Phase I enzymes, may bind transiently and re-bind in
a variety of conformations prior to the chemical reaction (e.g.,
oxidation). This hypothesis is supported by the relatively vast
size of binding pockets in many Phase I enzymes and the promiscuous
nature of many metabolic reactions. Metabolic switching can
potentially lead to different proportions of known metabolites as
well as altogether new metabolites. This new metabolic profile may
impart more or less toxicity.
[0179] The animal body expresses a variety of enzymes for the
purpose of eliminating foreign substances, such as therapeutic
agents, from its circulation system. Examples of such enzymes
include the cytochrome P450 enzymes ("CYPs"), esterases, proteases,
reductases, dehydrogenases, and monoamine oxidases, to react with
and convert these foreign substances to more polar intermediates or
metabolites for renal excretion. Some of the most common metabolic
reactions of pharmaceutical compounds involve the oxidation of a
carbon-hydrogen (C--H) bond to either a carbon-oxygen (C--O) or
carbon-carbon (C--C) pi-bond. The resultant metabolites may be
stable or unstable under physiological conditions, and can have
substantially different pharmacokinetic, pharmacodynamic, and acute
and long-term toxicity profiles relative to the parent compounds.
For many drugs, such oxidations are rapid. These drugs therefore
often require the administration of multiple or high daily
doses.
[0180] Therefore, isotopic enrichment at certain positions of a
compound provided herein will produce a detectable KIE that will
affect the pharmacokinetic, pharmacologic, and/or toxicological
profiles of a compound provided herein in comparison with a similar
compound having a natural isotopic composition.
[0181] Preparation of Compounds
[0182] The compounds provided herein can be prepared, isolated or
obtained by any method apparent to those of skill in the art.
Compounds provided herein can be prepared according to the
Exemplary Preparation Schemes provided below. Reaction conditions,
steps and reactants not provided in the Exemplary Preparation
Schemes would be apparent to, and known by, those skilled in the
art.
Exemplary Preparation Schemes
##STR00032##
##STR00033##
[0184] wherein one of R.sup.1 and R.sup.2 is hydrogen and P is a
protecting group such as dMTr
##STR00034##
[0185] wherein one of R.sup.1 and R.sup.2 is hydrogen and P is a
protecting group such as dMTr
##STR00035##
[0186] In the Exemplary Preparation Schemes, the variables are as
described in the context of Formula I to IV. Nucleosides can be
prepared or obtained according to the knowledge in the art.
Additional steps and reagents not provided in the Exemplary
Preparation Schemes would be known to those of skill in the art.
Exemplary methods of preparation are described in detail in the
Examples herein.
[0187] In the Exemplary Preparation Schemes, the variables are as
described in the context of Formula I to IV. Nucleosides can be
prepared or obtained according to the knowledge in the art.
Additional steps and reagents not provided in the Exemplary
Preparation Schemes would be known to those of skill in the art.
Exemplary methods of preparation are described in detail in the
Examples herein.
[0188] Pharmaceutical Compositions and Methods of
Administration
[0189] Compounds described herein can be formulated into
pharmaceutical compositions using methods available in the art and
those disclosed herein. Any of the compounds disclosed herein can
be provided in the appropriate pharmaceutical composition and be
administered by a suitable route of administration.
[0190] The methods provided herein encompass administering
pharmaceutical compositions containing at least one compound as
described herein, including a compound of general Formulas I-VIII,
if appropriate in the salt form, either used alone or in the form
of a combination with one or more compatible and pharmaceutically
acceptable carriers, such as diluents or adjuvants, or with another
anti-cancer agent.
[0191] In certain embodiments, the second agent can be formulated
or packaged with the compound provided herein. Of course, the
second agent will only be formulated with the compound provided
herein when, according to the judgment of those of skill in the
art, such co-formulation should not interfere with the activity of
either agent or the method of administration. In certain
embodiments, the compound provided herein and the second agent are
formulated separately. They can be packaged together, or packaged
separately, for the convenience of the practitioner of skill in the
art.
[0192] In clinical practice the active agents provided herein may
be administered by any conventional route, in particular orally,
parenterally, rectally or by inhalation (e.g. in the form of
aerosols). In certain embodiments, the compound provided herein is
administered orally.
[0193] Use may be made, as solid compositions for oral
administration, of tablets, pills, hard gelatin capsules, powders
or granules. In these compositions, the active product is mixed
with one or more inert diluents or adjuvants, such as sucrose,
lactose or starch.
[0194] These compositions can comprise substances other than
diluents, for example a lubricant, such as magnesium stearate, or a
coating intended for controlled release.
[0195] Use may be made, as liquid compositions for oral
administration, of solutions which are pharmaceutically acceptable,
suspensions, emulsions, syrups and elixirs containing inert
diluents, such as water or liquid paraffin. These compositions can
also comprise substances other than diluents, for example wetting,
sweetening or flavoring products.
[0196] The compositions for parenteral administration can be
emulsions or sterile solutions. Use may be made, as solvent or
vehicle, of propylene glycol, a polyethylene glycol, vegetable
oils, in particular olive oil, or injectable organic esters, for
example ethyl oleate. These compositions can also contain
adjuvants, in particular wetting, isotonizing, emulsifying,
dispersing and stabilizing agents. Sterilization can be carried out
in several ways, for example using a bacteriological filter, by
radiation or by heating. They can also be prepared in the form of
sterile solid compositions which can be dissolved at the time of
use in sterile water or any other injectable sterile medium.
[0197] The compositions for rectal administration are suppositories
or rectal capsules which contain, in addition to the active
principle, excipients such as cocoa butter, semi-synthetic
glycerides or polyethylene glycols.
[0198] The compositions can also be aerosols. For use in the form
of liquid aerosols, the compositions can be stable sterile
solutions or solid compositions dissolved at the time of use in
apyrogenic sterile water, in saline or any other pharmaceutically
acceptable vehicle. For use in the form of dry aerosols intended to
be directly inhaled, the active principle is finely divided and
combined with a water-soluble solid diluent or vehicle, for example
dextran, mannitol or lactose.
[0199] In certain embodiments, a composition provided herein is a
pharmaceutical composition or a single unit dosage form.
Pharmaceutical compositions and single unit dosage forms provided
herein comprise a prophylactically or therapeutically effective
amount of one or more prophylactic or therapeutic agents (e.g., a
compound provided herein, or other prophylactic or therapeutic
agent), and a typically one or more pharmaceutically acceptable
carriers or excipients. In a specific embodiment and in this
context, the term "pharmaceutically acceptable" means approved by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals, and more particularly in humans. The term
"carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant
(complete and incomplete)), excipient, or vehicle with which the
therapeutic is administered. Such pharmaceutical carriers can be
sterile liquids, such as water and oils, including those of
petroleum, animal, vegetable or synthetic origin, such as peanut
oil, soybean oil, mineral oil, sesame oil and the like. Water can
be used as a carrier when the pharmaceutical composition is
administered intravenously. Saline solutions and aqueous dextrose
and glycerol solutions can also be employed as liquid carriers,
particularly for injectable solutions. Examples of suitable
pharmaceutical carriers are described in "Remington's
Pharmaceutical Sciences" by E. W. Martin.
[0200] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well-known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients include starch, glucose, lactose, sucrose,
gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,
glycerol monostearate, talc, sodium chloride, dried skim milk,
glycerol, propylene, glycol, water, ethanol and the like. Whether a
particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of
factors well known in the art including, but not limited to, the
way in which the dosage form will be administered to a subject and
the specific active ingredients in the dosage form. The composition
or single unit dosage form, if desired, can also contain minor
amounts of wetting or emulsifying agents, or pH buffering
agents.
[0201] Lactose free compositions provided herein can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In
general, lactose free compositions comprise an active ingredient, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Exemplary lactose free dosage
forms comprise an active ingredient, microcrystalline cellulose,
pre gelatinized starch, and magnesium stearate.
[0202] Further encompassed herein are anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long term storage in
order to determine characteristics such as shelf life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
New York, 1995, pp. 379 80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0203] Anhydrous pharmaceutical compositions and dosage forms
provided herein can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine can be anhydrous if substantial contact with
moisture and/or humidity during manufacturing, packaging, and/or
storage is expected.
[0204] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions can be packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastics, unit
dose containers (e.g., vials), blister packs, and strip packs.
[0205] Further provided are pharmaceutical compositions and dosage
forms that comprise one or more compounds that reduce the rate by
which an active ingredient will decompose. Such compounds, which
are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
[0206] The pharmaceutical compositions and single unit dosage forms
can take the form of solutions, suspensions, emulsion, tablets,
pills, capsules, powders, sustained-release formulations and the
like. Oral formulation can include standard carriers such as
pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
Such compositions and dosage forms will contain a prophylactically
or therapeutically effective amount of a prophylactic or
therapeutic agent, in certain embodiments, in purified form,
together with a suitable amount of carrier so as to provide the
form for proper administration to the subject. The formulation
should suit the mode of administration. In a certain embodiment,
the pharmaceutical compositions or single unit dosage forms are
sterile and in suitable form for administration to a subject, for
example, an animal subject, such as a mammalian subject, for
example, a human subject.
[0207] A pharmaceutical composition is formulated to be compatible
with its intended route of administration. Examples of routes of
administration include, but are not limited to, parenteral, e.g.,
intravenous, intradermal, subcutaneous, intramuscular,
subcutaneous, oral, buccal, sublingual, inhalation, intranasal,
transdermal, topical, transmucosal, intra-tumoral, intra-synovial
and rectal administration. In a specific embodiment, the
composition is formulated in accordance with routine procedures as
a pharmaceutical composition adapted for intravenous, subcutaneous,
intramuscular, oral, intranasal or topical administration to human
beings. In an embodiment, a pharmaceutical composition is
formulated in accordance with routine procedures for subcutaneous
administration to human beings. Typically, compositions for
intravenous administration are solutions in sterile isotonic
aqueous buffer. Where necessary, the composition may also include a
solubilizing agent and a local anesthetic such as lignocamne to
ease pain at the site of the injection.
[0208] Examples of dosage forms include, but are not limited to:
tablets; caplets; capsules, such as soft elastic gelatin capsules;
cachets; troches; lozenges; dispersions; suppositories; ointments;
cataplasms (poultices); pastes; powders; dressings; creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or
inhalers); gels; liquid dosage forms suitable for oral or mucosal
administration to a subject, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions, oil in water emulsions, or a
water in oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a subject;
and sterile solids (e.g., crystalline or amorphous solids) that can
be reconstituted to provide liquid dosage forms suitable for
parenteral administration to a subject.
[0209] The composition, shape, and type of dosage forms provided
herein will typically vary depending on their use. For example, a
dosage form used in the initial treatment of a cancer may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the maintenance treatment of
the same cancer. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease
or disorder. These and other ways in which specific dosage forms
encompassed herein will vary from one another will be readily
apparent to those skilled in the art. See, e.g., Remington's
Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa.
(2000).
[0210] Generally, the ingredients of compositions are supplied
either separately or mixed together in unit dosage form, for
example, as a dry lyophilized powder or water free concentrate in a
hermetically sealed container such as an ampoule or sachette
indicating the quantity of active agent. Where the composition is
to be administered by infusion, it can be dispensed with an
infusion bottle containing sterile pharmaceutical grade water or
saline. Where the composition is administered by injection, an
ampoule of sterile water for injection or saline can be provided so
that the ingredients may be mixed prior to administration.
[0211] Typical dosage forms comprise a compound provided herein, or
a pharmaceutically acceptable salt, solvate or hydrate thereof lie
within the range of from about 0.1 mg to about 1000 mg per day,
given as a single once-a-day dose in the morning or as divided
doses throughout the day taken with food. Particular dosage forms
can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0,
15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active
compound.
[0212] Oral Dosage Forms
[0213] Pharmaceutical compositions that are suitable for oral
administration can be presented as discrete dosage forms, such as,
but are not limited to, tablets (e.g., chewable tablets), caplets,
capsules, and liquids (e.g., flavored syrups). Such dosage forms
contain predetermined amounts of active ingredients, and may be
prepared by methods of pharmacy well known to those skilled in the
art. See generally, Remington's Pharmaceutical Sciences, 20th ed.,
Mack Publishing, Easton Pa. (2000).
[0214] In certain embodiments, the oral dosage forms are solid and
prepared under anhydrous conditions with anhydrous ingredients, as
described in detail herein. However, the scope of the compositions
provided herein extends beyond anhydrous, solid oral dosage forms.
As such, further forms are described herein.
[0215] Typical oral dosage forms are prepared by combining the
active ingredient(s) in an intimate admixture with at least one
excipient according to conventional pharmaceutical compounding
techniques. Excipients can take a wide variety of forms depending
on the form of preparation desired for administration. For example,
excipients suitable for use in oral liquid or aerosol dosage forms
include, but are not limited to, water, glycols, oils, alcohols,
flavoring agents, preservatives, and coloring agents. Examples of
excipients suitable for use in solid oral dosage forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not
limited to, starches, sugars, micro crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0216] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or non-aqueous techniques. Such
dosage forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0217] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0218] Examples of excipients that can be used in oral dosage forms
include, but are not limited to, binders, fillers, disintegrants,
and lubricants. Binders suitable for use in pharmaceutical
compositions and dosage forms include, but are not limited to, corn
starch, potato starch, or other starches, gelatin, natural and
synthetic gums such as acacia, sodium alginate, alginic acid, other
alginates, powdered tragacanth, guar gum, cellulose and its
derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0219] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions is typically present in from about 50 to about 99
weight percent of the pharmaceutical composition or dosage
form.
[0220] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL PH 101, AVICEL PH
103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation,
American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and
mixtures thereof. A specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC 581. Suitable anhydrous or low moisture excipients or
additives include AVICEL PH 103.TM. and Starch 1500 LM.
[0221] Disintegrants are used in the compositions to provide
tablets that disintegrate when exposed to an aqueous environment.
Tablets that contain too much disintegrant may disintegrate in
storage, while those that contain too little may not disintegrate
at a desired rate or under the desired conditions. Thus, a
sufficient amount of disintegrant that is neither too much nor too
little to detrimentally alter the release of the active ingredients
should be used to form solid oral dosage forms. The amount of
disintegrant used varies based upon the type of formulation, and is
readily discernible to those of ordinary skill in the art. Typical
pharmaceutical compositions comprise from about 0.5 to about 15
weight percent of disintegrant, specifically from about 1 to about
5 weight percent of disintegrant.
[0222] Disintegrants that can be used in pharmaceutical
compositions and dosage forms include, but are not limited to,
agar, alginic acid, calcium carbonate, microcrystalline cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium
starch glycolate, potato or tapioca starch, pre gelatinized starch,
other starches, clays, other algins, other celluloses, gums, and
mixtures thereof.
[0223] Lubricants that can be used in pharmaceutical compositions
and dosage forms include, but are not limited to, calcium stearate,
magnesium stearate, mineral oil, light mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl
laureate, agar, and mixtures thereof. Additional lubricants
include, for example, a syloid silica gel (AEROSIL 200,
manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated
aerosol of synthetic silica (marketed by Degussa Co. of Plano,
Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot
Co. of Boston, Mass.), and mixtures thereof. If used at all,
lubricants are typically used in an amount of less than about 1
weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0224] Delayed Release Dosage Forms
[0225] Active ingredients such as the compounds provided herein can
be administered by controlled release means or by delivery devices
that are well known to those of ordinary skill in the art. Examples
include, but are not limited to, those described in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719;
5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;
5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356;
5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943;
6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961;
6,589,548; 6,613,358; and 6,699,500; each of which is incorporated
herein by reference in its entirety. Such dosage forms can be used
to provide slow or controlled release of one or more active
ingredients using, for example, hydropropylmethyl cellulose, other
polymer matrices, gels, permeable membranes, osmotic systems,
multilayer coatings, microparticles, liposomes, microspheres, or a
combination thereof to provide the desired release profile in
varying proportions. Suitable controlled release formulations known
to those of ordinary skill in the art, including those described
herein, can be readily selected for use with the active ingredients
provided herein. Thus encompassed herein are single unit dosage
forms suitable for oral administration such as, but not limited to,
tablets, capsules, gelcaps, and caplets that are adapted for
controlled release.
[0226] All controlled release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled release formulations include extended activity of the
drug, reduced dosage frequency, and increased subject compliance.
In addition, controlled release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0227] Most controlled release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0228] In certain embodiments, the drug may be administered using
intravenous infusion, an implantable osmotic pump, a transdermal
patch, liposomes, or other modes of administration. In certain
embodiments, a pump may be used (see, Sefton, CRC Crit. Ref Biomed.
Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek
et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,
polymeric materials can be used. In yet another embodiment, a
controlled release system can be placed in a subject at an
appropriate site determined by a practitioner of skill, i.e., thus
requiring only a fraction of the systemic dose (see, e.g., Goodson,
Medical Applications of Controlled Release, vol. 2, pp. 115-138
(1984)). Other controlled release systems are discussed in the
review by Langer (Science 249:1527-1533 (1990)). The active
ingredient can be dispersed in a solid inner matrix, e.g.,
polymethylmethacrylate, polybutylmethacrylate, plasticized or
unplasticized polyvinylchloride, plasticized nylon, plasticized
polyethyleneterephthalate, natural rubber, polyisoprene,
polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate
copolymers, silicone rubbers, polydimethylsiloxanes, silicone
carbonate copolymers, hydrophilic polymers such as hydrogels of
esters of acrylic and methacrylic acid, collagen, cross-linked
polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl
acetate, that is surrounded by an outer polymeric membrane, e.g.,
polyethylene, polypropylene, ethylene/propylene copolymers,
ethylene/ethyl acrylate copolymers, ethylene/vinylacetate
copolymers, silicone rubbers, polydimethyl siloxanes, neoprene
rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride
copolymers with vinyl acetate, vinylidene chloride, ethylene and
propylene, ionomer polyethylene terephthalate, butyl rubber
epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer, that is insoluble in body
fluids. The active ingredient then diffuses through the outer
polymeric membrane in a release rate controlling step. The
percentage of active ingredient in such parenteral compositions is
highly dependent on the specific nature thereof, as well as the
needs of the subject.
[0229] Parenteral Dosage Forms
[0230] In certain embodiments, provided are parenteral dosage
forms. Parenteral dosage forms can be administered to subjects by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
subjects' natural defenses against contaminants, parenteral dosage
forms are typically, sterile or capable of being sterilized prior
to administration to a subject. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0231] Suitable vehicles that can be used to provide parenteral
dosage forms are well known to those skilled in the art. Examples
include, but are not limited to: Water for Injection USP; aqueous
vehicles such as, but not limited to, Sodium Chloride Injection,
Ringer's Injection, Dextrose Injection, Dextrose and Sodium
Chloride Injection, and Lactated Ringer's Injection; water miscible
vehicles such as, but not limited to, ethyl alcohol, polyethylene
glycol, and polypropylene glycol; and non-aqueous vehicles such as,
but not limited to, corn oil, cottonseed oil, peanut oil, sesame
oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[0232] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms.
[0233] Transdermal, Topical & Mucosal Dosage Forms
[0234] Also provided are transdermal, topical, and mucosal dosage
forms. Transdermal, topical, and mucosal dosage forms include, but
are not limited to, ophthalmic solutions, sprays, aerosols, creams,
lotions, ointments, gels, solutions, emulsions, suspensions, or
other forms known to one of skill in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16.sup.th, 18th and 20.sup.th
eds., Mack Publishing, Easton Pa. (1980, 1990 & 2000); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0235] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed herein are well known to those
skilled in the pharmaceutical arts, and depend on the particular
tissue to which a given pharmaceutical composition or dosage form
will be applied. With that fact in mind, typical excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane 1,3 diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form
lotions, tinctures, creams, emulsions, gels or ointments, which are
nontoxic and pharmaceutically acceptable. Moisturizers or
humectants can also be added to pharmaceutical compositions and
dosage forms if desired. Examples of such additional ingredients
are well known in the art. See, e.g., Remington's Pharmaceutical
Sciences, 16.sup.th, 18th and 20.sup.th eds., Mack Publishing,
Easton Pa. (1980, 1990 & 2000).
[0236] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients provided. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various water
soluble or insoluble sugar esters such as Tween 80 (polysorbate 80)
and Span 60 (sorbitan monostearate).
[0237] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery enhancing or penetration
enhancing agent. Different salts, hydrates or solvates of the
active ingredients can be used to further adjust the properties of
the resulting composition.
[0238] Dosage and Unit Dosage Forms
[0239] In human therapeutics, the doctor will determine the
posology which he considers most appropriate according to a
preventive or curative treatment and according to the age, weight,
stage of the cancer and other factors specific to the subject to be
treated. In certain embodiments, doses are from about 1 to about
1000 mg per day for an adult, or from about 5 to about 250 mg per
day or from about 10 to 50 mg per day for an adult. In certain
embodiments, doses are from about 5 to about 400 mg per day or 25
to 200 mg per day per adult. In certain embodiments, dose rates of
from about 50 to about 500 mg per day are also contemplated.
[0240] In further aspects, provided are methods of treating or
preventing a cancer in a subject by administering, to a subject in
need thereof, an effective amount of a compound provided herein, or
a pharmaceutically acceptable salt thereof. The amount of the
compound or composition which will be effective in the prevention
or treatment of a disorder or one or more symptoms thereof will
vary with the nature and severity of the disease or condition, and
the route by which the active ingredient is administered. The
frequency and dosage will also vary according to factors specific
for each subject depending on the specific therapy (e.g.,
therapeutic or prophylactic agents) administered, the severity of
the disorder, disease, or condition, the route of administration,
as well as age, body, weight, response, and the past medical
history of the subject. Effective doses may be extrapolated from
dose-response curves derived from in vitro or animal model test
systems.
[0241] In certain embodiments, exemplary doses of a composition
include milligram or microgram amounts of the active compound per
kilogram of subject or sample weight (e.g., about 10 micrograms per
kilogram to about 50 milligrams per kilogram, about 100 micrograms
per kilogram to about 25 milligrams per kilogram, or about 100
microgram per kilogram to about 10 milligrams per kilogram). For
compositions provided herein, in certain embodiments, the dosage
administered to a subject is 0.140 mg/kg to 3 mg/kg of the
subject's body weight, based on weight of the active compound. In
certain embodiments, the dosage administered to a subject is
between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50
mg/kg of the subject's body weight.
[0242] In certain embodiments, the recommended daily dose range of
a composition provided herein for the conditions described herein
lie within the range of from about 0.1 mg to about 1000 mg per day,
given as a single once-a-day dose or as divided doses throughout a
day. In certain embodiments, the daily dose is administered twice
daily in equally divided doses. In certain embodiments, a daily
dose range should be from about 10 mg to about 200 mg per day, in
other embodiments, between about 10 mg and about 150 mg per day, in
further embodiments, between about 25 and about 100 mg per day. It
may be necessary to use dosages of the active ingredient outside
the ranges disclosed herein in some cases, as will be apparent to
those of ordinary skill in the art. Furthermore, it is noted that
the clinician or treating physician will know how and when to
interrupt, adjust, or terminate therapy in conjunction with subject
response.
[0243] Different therapeutically effective amounts may be
applicable for different diseases and conditions, as will be
readily known by those of ordinary skill in the art. Similarly,
amounts sufficient to prevent, manage, treat or ameliorate such
disorders, but insufficient to cause, or sufficient to reduce,
adverse effects associated with the composition provided herein are
also encompassed by the herein described dosage amounts and dose
frequency schedules. Further, when a subject is administered
multiple dosages of a composition provided herein, not all of the
dosages need be the same. For example, the dosage administered to
the subject may be increased to improve the prophylactic or
therapeutic effect of the composition or it may be decreased to
reduce one or more side effects that a particular subject is
experiencing.
[0244] In certain embodiment, the dosage of the composition
provided herein, based on weight of the active compound,
administered to prevent, treat, manage, or ameliorate a disorder,
or one or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg,
2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg
or more of a subject's body weight. In another embodiment, the
dosage of the composition or a composition provided herein
administered to prevent, treat, manage, or ameliorate a disorder,
or one or more symptoms thereof in a subject is a unit dose of 0.1
mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg,
0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5
mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg,
0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg,
0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg
to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
[0245] In certain embodiments, treatment or prevention can be
initiated with one or more loading doses of a compound or
composition provided herein followed by one or more maintenance
doses. In such embodiments, the loading dose can be, for instance,
about 60 to about 400 mg per day, or about 100 to about 200 mg per
day for one day to five weeks. The loading dose can be followed by
one or more maintenance doses. In certain embodiments, each
maintenance does is, independently, about from about 10 mg to about
200 mg per day, between about 25 mg and about 150 mg per day, or
between about 25 and about 80 mg per day. Maintenance doses can be
administered daily and can be administered as single doses, or as
divided doses.
[0246] In certain embodiments, a dose of a compound or composition
provided herein can be administered to achieve a steady-state
concentration of the active ingredient in blood or serum of the
subject. The steady-state concentration can be determined by
measurement according to techniques available to those of skill or
can be based on the physical characteristics of the subject such as
height, weight and age. In certain embodiments, a sufficient amount
of a compound or composition provided herein is administered to
achieve a steady-state concentration in blood or serum of the
subject of from about 300 to about 4000 ng/mL, from about 400 to
about 1600 ng/mL, or from about 600 to about 1200 ng/mL. In some
embodiments, loading doses can be administered to achieve
steady-state blood or serum concentrations of about 1200 to about
8000 ng/mL, or about 2000 to about 4000 ng/mL for one to five days.
In certain embodiments, maintenance doses can be administered to
achieve a steady-state concentration in blood or serum of the
subject of from about 300 to about 4000 ng/mL, from about 400 to
about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
[0247] In certain embodiments, administration of the same
composition may be repeated and the administrations may be
separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15
days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In other embodiments, administration of the same prophylactic or
therapeutic agent may be repeated and the administration may be
separated by at least at least 1 day, 2 days, 3 days, 5 days, 10
days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6
months.
[0248] In certain aspects, provided herein are unit dosages
comprising a compound, or a pharmaceutically acceptable salt
thereof, in a form suitable for administration. Such forms are
described in detail herein. In certain embodiments, the unit dosage
comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active
ingredient. In particular embodiments, the unit dosages comprise
about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active
ingredient. Such unit dosages can be prepared according to
techniques familiar to those of skill in the art.
[0249] The dosages of the second agents are to be used in the
combination therapies provided herein. In certain embodiments,
dosages lower than those which have been or are currently being
used to prevent or treat cancer are used in the combination
therapies provided herein. The recommended dosages of second agents
can be obtained from the knowledge of those of skill. For those
second agents that are approved for clinical use, recommended
dosages are described in, for example, Hardman et al., eds., 1996,
Goodman & Gilman's The Pharmacological Basis Of Basis Of
Therapeutics 9.sup.th Ed, Mc-Graw-Hill, New York; Physician's Desk
Reference (PDR) 57.sup.th Ed., 2003, Medical Economics Co., Inc.,
Montvale, N.J., which are incorporated herein by reference in its
entirety.
[0250] In various embodiments, the therapies (e.g., a compound
provided herein and the second agent) are administered less than 5
minutes apart, less than 30 minutes apart, 1 hour apart, at about 1
hour apart, at about 1 to about 2 hours apart, at about 2 hours to
about 3 hours apart, at about 3 hours to about 4 hours apart, at
about 4 hours to about 5 hours apart, at about 5 hours to about 6
hours apart, at about 6 hours to about 7 hours apart, at about 7
hours to about 8 hours apart, at about 8 hours to about 9 hours
apart, at about 9 hours to about 10 hours apart, at about 10 hours
to about 11 hours apart, at about 11 hours to about 12 hours apart,
at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24
hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52
hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours
apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or
96 hours to 120 hours apart. In various embodiments, the therapies
are administered no more than 24 hours apart or no more than 48
hours apart. In certain embodiments, two or more therapies are
administered within the same patient visit. In other embodiments,
the compound provided herein and the second agent are administered
concurrently.
[0251] In other embodiments, the compound provided herein and the
second agent are administered at about 2 to 4 days apart, at about
4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks
apart, or more than 2 weeks apart.
[0252] In certain embodiments, administration of the same agent may
be repeated and the administrations may be separated by at least 1
day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2
months, 75 days, 3 months, or 6 months. In other embodiments,
administration of the same agent may be repeated and the
administration may be separated by at least at least 1 day, 2 days,
3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75
days, 3 months, or 6 months.
[0253] In certain embodiments, a compound provided herein and a
second agent are administered to a patient, for example, a mammal,
such as a human, in a sequence and within a time interval such that
the compound provided herein can act together with the other agent
to provide an increased benefit than if they were administered
otherwise. For example, the second active agent can be administered
at the same time or sequentially in any order at different points
in time; however, if not administered at the same time, they should
be administered sufficiently close in time so as to provide the
desired therapeutic or prophylactic effect. In certain embodiments,
the compound provided herein and the second active agent exert
their effect at times which overlap. Each second active agent can
be administered separately, in any appropriate form and by any
suitable route. In other embodiments, the compound provided herein
is administered before, concurrently or after administration of the
second active agent.
[0254] In certain embodiments, the compound provided herein and the
second agent are cyclically administered to a patient. Cycling
therapy involves the administration of a first agent (e.g., a first
prophylactic or therapeutic agents) for a period of time, followed
by the administration of a second agent and/or third agent (e.g., a
second and/or third prophylactic or therapeutic agents) for a
period of time and repeating this sequential administration.
Cycling therapy can reduce the development of resistance to one or
more of the therapies, avoid or reduce the side effects of one of
the therapies, and/or improve the efficacy of the treatment.
[0255] In certain embodiments, the compound provided herein and the
second active agent are administered in a cycle of less than about
3 weeks, about once every two weeks, about once every 10 days or
about once every week. One cycle can comprise the administration of
a compound provided herein and the second agent by infusion over
about 90 minutes every cycle, about 1 hour every cycle, about 45
minutes every cycle. Each cycle can comprise at least 1 week of
rest, at least 2 weeks of rest, at least 3 weeks of rest. The
number of cycles administered is from about 1 to about 12 cycles,
more typically from about 2 to about 10 cycles, and more typically
from about 2 to about 8 cycles.
[0256] In other embodiments, courses of treatment are administered
concurrently to a patient, i.e., individual doses of the second
agent are administered separately yet within a time interval such
that the compound provided herein can work together with the second
active agent. For example, one component can be administered once
per week in combination with the other components that can be
administered once every two weeks or once every three weeks. In
other words, the dosing regimens are carried out concurrently even
if the therapeutics are not administered simultaneously or during
the same day.
[0257] The second agent can act additively or synergistically with
the compound provided herein. In certain embodiments, the compound
provided herein is administered concurrently with one or more
second agents in the same pharmaceutical composition. In another
embodiment, a compound provided herein is administered concurrently
with one or more second agents in separate pharmaceutical
compositions. In still another embodiment, a compound provided
herein is administered prior to or subsequent to administration of
a second agent. Also contemplated are administration of a compound
provided herein and a second agent by the same or different routes
of administration, e.g., oral and parenteral. In certain
embodiments, when the compound provided herein is administered
concurrently with a second agent that potentially produces adverse
side effects including, but not limited to, toxicity, the second
active agent can advantageously be administered at a dose that
falls below the threshold that the adverse side effect is
elicited.
[0258] Kits
[0259] Also provided are kits for use in methods of treatment of a
cancer, for example a liver cancer such as hepatocellular
carcinoma, cholangiocarcinoma, or biliary tract cancer. In certain
embodiments, the cancer is breast cancer, ovarian cancer, lung
cancer, pancreatic cancer or leukemic cancer. The kits can include
a compound or composition provided herein, a second agent or
composition, and instructions providing information to a health
care provider regarding usage for treating the disorder.
Instructions may be provided in printed form or in the form of an
electronic medium such as a floppy disc, CD, or DVD, or in the form
of a website address where such instructions may be obtained. A
unit dose of a compound or composition provided herein, or a second
agent or composition, can include a dosage such that when
administered to a subject, a therapeutically or prophylactically
effective plasma level of the compound or composition can be
maintained in the subject for at least 1 days. In some embodiments,
a compound or composition can be included as a sterile aqueous
pharmaceutical composition or dry powder (e.g., lyophilized)
composition.
[0260] In some embodiments, suitable packaging is provided. As used
herein, "packaging" includes a solid matrix or material customarily
used in a system and capable of holding within fixed limits a
compound provided herein and/or a second agent suitable for
administration to a subject. Such materials include glass and
plastic (e.g., polyethylene, polypropylene, and polycarbonate)
bottles, vials, paper, plastic, and plastic-foil laminated
envelopes and the like. If e-beam sterilization techniques are
employed, the packaging should have sufficiently low density to
permit sterilization of the contents.
[0261] Methods of Use
[0262] In one embodiment is a compound or a pharmaceutically
acceptable salt, solvate, stereoisomeric form, tautomeric form or
polymorphic form thereof for use in therapy.
[0263] Provided herein is a method for treating cancer in a
subject, which comprises contacting the subject with a
therapeutically effective amount of a nucleotide analog disclosed
herein, e.g., a compound of Formulas I-VIII, including a single
enantiomer, a mixture of an enantiomeric pair, an individual
diastereomer, a mixture of diastereomers, or a tautomeric form
thereof; or a pharmaceutically acceptable salt, solvate, prodrug,
phosphate, or active metabolite thereof. In certain embodiments,
the cancer is selected from liver cancer, breast cancer, ovarian
cancer, lung cancer, pancreatic cancer or leukemic cancer. In an
embodiment the cancer is liver cancer. Liver cancers which can be
treated include primary and secondary liver cancers. In particular
embodiments, the liver cancer is hepatocellular carcinoma,
cholangiocarcinoma, or biliary tract cancer. In particular
embodiments, the liver cancer is a metastasis in the liver
originated from other cancers (such as colon cancer, pancreatic
cancer, etc.).
[0264] Provided herein is a method for inhibiting the growth of a
cancer cell, which comprises contacting the cell with a
therapeutically effective amount of a compound disclosed herein,
e.g., a compound of Formulas I-VIII, including a single enantiomer,
a mixture of an enantiomeric pair, an individual diastereomer, a
mixture of diastereomers, or a tautomeric form thereof; or a
pharmaceutically acceptable salt, solvate, prodrug, phosphate, or
active metabolite thereof. In certain embodiments, the cancer is
selected from liver cancer, breast cancer, ovarian cancer, lung
cancer, pancreatic cancer or leukemic cancer. In an embodiment the
cancer is liver cancer. In certain embodiments, the liver cancer is
hepatocellular carcinoma, cholangiocarcinoma, or biliary tract
cancer. In particular embodiments, the cancer is hepatocellular
carcinoma.
[0265] Provided herein is a method for inhibiting replication of a
cancer cell, which comprises contacting the cell with a
therapeutically effective amount of a compound disclosed herein,
e.g., a compound of Formulas I-VIII, including a single enantiomer,
a mixture of an enantiomeric pair, an individual diastereomer, a
mixture of diastereomers, or a tautomeric form thereof; or a
pharmaceutically acceptable salt, solvate, prodrug, phosphate, or
active metabolite thereof. In certain embodiments, the cancer is
selected from liver cancer, breast cancer, ovarian cancer, lung
cancer, pancreatic cancer or leukemic cancer. In an embodiment the
cancer is liver cancer. In certain embodiments, the liver cancer is
hepatocellular carcinoma, cholangiocarcinoma, or biliary tract
cancer. In particular embodiments, the cancer is hepatocellular
carcinoma.
[0266] Provided herein is a method for inhibiting the growth of a
tumor, which comprises contacting the tumor with a compound
disclosed herein, e.g., a compound of Formulas I-VIII, including a
single enantiomer, a mixture of an enantiomeric pair, an individual
diastereomer, a mixture of diastereomers, or a tautomeric form
thereof; or a pharmaceutically acceptable salt, solvate, prodrug,
phosphate, or active metabolite thereof. In certain embodiments,
the tumor is selected from a liver tumor, breast tumor, ovarian
tumor, lung tumor, pancreatic tumor or leukemic tumor. In an
embodiment the tumor is liver tumor. In certain embodiments, the
liver tumor is hepatocellular carcinoma, cholangiocarcinoma, or
biliary tract cancer. In particular embodiments, the tumor is
hepatocellular carcinoma.
[0267] In certain embodiments, provided herein are methods for the
treatment and/or prophylaxis of a subject with cancer that includes
the administration of an effective amount of a nucleoside compound
disclosed herein, e.g., a nucleoside compound of Formulas I-VIII,
including a single enantiomer, a mixture of an enantiomeric pair,
an individual diastereomer, a mixture of diastereomers, or a
tautomeric form thereof or a pharmaceutically acceptable salt,
solvate, prodrug, phosphate, or active metabolite thereof. In
certain embodiments, the cancer is selected from liver cancer,
breast cancer, ovarian cancer, lung cancer, pancreatic cancer or
leukemic cancer. In an embodiment the cancer is liver cancer. In
certain embodiments, the liver cancer is hepatocellular carcinoma,
cholangiocarcinoma, or biliary tract cancer. In particular
embodiments, the cancer is hepatocellular carcinoma.
[0268] In certain embodiments, provided herein are methods for
treating a cancer in a subject. In certain embodiments, the methods
encompass the step of administering to the subject in need thereof
an amount of a compound effective for the treatment or prevention
of a cancer in combination with a second agent effective for the
treatment or prevention of the cancer. The compound can be any
compound as described herein, and the second agent can be any
second agent described in the art or herein. In certain
embodiments, the compound is in the form of a pharmaceutical
composition or dosage form, as described elsewhere herein. In
certain embodiments, the cancer is selected from liver cancer,
breast cancer, ovarian cancer, lung cancer, pancreatic cancer or
leukemic cancer. In an embodiment the cancer is liver cancer. In
certain embodiments, the liver cancer is hepatocellular carcinoma,
cholangiocarcinoma, or biliary tract cancer. In particular
embodiments, the cancer is hepatocellular carcinoma.
[0269] In certain embodiments, provided herein are methods for the
treatment and/or prophylaxis of a subject with cancer that includes
the administration of an effective amount of a compounds provided
herein, or a pharmaceutically acceptable salt thereof. In certain
embodiments, provided herein are methods for treating a cancer in a
subject. In certain embodiments, the methods encompass the step of
administering to the subject in need thereof an amount of a
compound effective for the treatment or prevention of a cancer in
combination with a second agent effective for the treatment or
prevention of the liver cancer. The compound can be any compound as
described herein, and the second agent can be any second agent
described in the art or herein. In certain embodiments, the
compound is in the form of a pharmaceutical composition or dosage
form, as described elsewhere herein. In certain embodiments, the
cancer is selected from liver cancer, breast cancer, ovarian
cancer, lung cancer, pancreatic cancer or leukemic cancer. In an
embodiment the cancer is liver cancer. In certain embodiments, the
liver cancer is hepatocellular carcinoma, cholangiocarcinoma, or
biliary tract cancer. In particular embodiments, the cancer is
hepatocellular carcinoma.
[0270] In an embodiment, the cancers which can be treated by the
compounds described herein include, but are not limited to, Acute
Lymphoblastic Leukemia; Acute Myeloid Leukemia; Adrenocortical
Carcinoma; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal
Cancer; Astrocytoma; Bile Duct Cancer; Bladder Cancer; Bone Cancer,
Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma;
Brain Tumor, Cerebellar Astrocytoma; Brain Tumor, Cerebral
Astrocytoma/Malignant Glioma; Brain Tumor, Ependymoma; Brain Tumor,
Medulloblastoma; Brain Tumor, Supratentorial Primitive
Neuroectodermal Tumors; Brain Tumor, Visual Pathway and
Hypothalamic Glioma; Breast Cancer; Bronchial Adenomas/Carcinoids;
Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Carcinoma,
Adrenocortical; Carcinoma, Islet Cell; Central Nervous System
Lymphoma, Primary; Cerebral Astrocytoma/Malignant Glioma; Cervical
Cancer; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia;
Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon
Sheaths; Colon Cancer; Colorectal Cancer; Cutaneous T-Cell
Lymphoma; Endometrial Cancer; Ependymoma; Epithelial Cancer,
Ovarian; Esophageal Cancer; Esophageal Cancer; Ewing's Family of
Tumors; Extracranial Germ Cell Tumor; Extrahepatic Bile Duct
Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer,
Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer;
Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial,
Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian;
Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem;
Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell
Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer;
Hodgkin's Lymphoma; Hypopharyngeal Cancer; Hypothalamic and Visual
Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma
(Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal
Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid;
Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous;
Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer;
Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic
Leukemia; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System
(Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's;
Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's;
Lymphoma, Primary Central Nervous System; Macroglobulinemia,
Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma;
Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma,
Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant;
Metastatic Squamous Neck Cancer with Occult Primary; Multiple
Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma
Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes;
Myelogenous Leukemia, Chronic; Myeloid Leukemia; Myeloma, Multiple;
Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal
Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's
Lymphoma; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity and
Lip Cancer; Oropharyngeal Cancer; steosarcoma/Malignant Fibrous
Histiocytoma of Bone; Ovarian Epithelial Cancer; Ovarian Germ Cell
Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer;
Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile
Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive
Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell
Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and
Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and
Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma;
Primary Liver Cancer; Prostate Cancer; Rectal Cancer; Renal Cell
(Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer;
Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Sarcoma,
Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma
(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,
Soft Tissue; Sezary Syndrome; Skin Cancer; Skin Cancer (Melanoma);
Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small
Intestine Cancer; Soft Tissue Sarcoma; Squamous Neck Cancer with
Occult Primary, Metastatic; Stomach (Gastric) Cancer;
Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma,
Cutaneous; Testicular Cancer; Thymoma, Malignant; Thyroid Cancer;
Transitional Cell Cancer of the Renal Pelvis and Ureter;
Trophoblastic Tumor, Gestational; Ureter and Renal Pelvis,
Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal
Cancer; Visual Pathway and Hypothalamic Glioma; Vulvar Cancer;
Waldenstrom's Macro globulinemia; and Wilms' Tumor.
[0271] In one embodiment, a cancer potentially associated with
mutant IDH enzyme activity is brain cancer, such as an astrocytic
tumor (e.g., pilocytic astrocytoma, subependymal giant-cell
astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma,
anaplastic astrocytoma, astrocytoma, giant cell glioblastoma,
glioblastoma, secondary glioblastoma, primary adult glioblastoma,
and primary pediatric glioblastoma); oligodendroglial tumor (e.g.,
oligodendroglioma, and anaplastic oligodendroglioma);
oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic
oligoastrocytoma); ependymoma (e.g., myxopapillary ependymoma, and
anaplastic ependymoma); medulloblastoma; primitive neuroectodermal
tumor, schwannoma, meningioma, meatypical meningioma, anaplastic
meningioma; and pituitary adenoma. In another embodiment, the brain
cancer is glioma, glioblastoma multiforme, paraganglioma, or
suprantentorial primordial neuroectodermal tumors (sPNET).
[0272] In another embodiment, a cancer potentially associated with
mutant IDH enzyme activity is leukemia, such as acute myeloid
leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous
leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML,
post-MDS AML, del(5q)-associated high risk MDS or AML, blast-phase
chronic myelogenous leukemia, angioimmunoblastic lymphoma and acute
lymphoblastic leukemia.
[0273] In one embodiment, a cancer potentially associated with
mutant IDH enzyme activity is skin cancer, including melanoma. In
another embodiment, a cancer potentially associated with mutant IDH
enzyme activity is prostate cancer, breast cancer, thyroid cancer,
colon cancer, or lung cancer. In another embodiment, a cancer
potentially associated with mutant IDH enzyme activity is sarcoma,
including central chondrosarcoma, central and periosteal chondroma,
and fibrosarcoma. In another embodiment, a cancer potentially
associated with mutant IDH enzyme activity is
cholangiocarcinoma.
[0274] In certain embodiments, the compounds described herein can
be used to treat a proliferative disease, for example a carcinoma,
including, but not limited to, Kit-mediated carcinomas,
adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma,
teratocarcinoma, head and neck cancer, brain cancer, intracranial
carcinoma, glioblastoma (including PDGFR-mediated glioblastoma),
glioblastoma multiforme (including PDGFR-mediated glioblastoma
multiforme), neuroblastoma, cancer of the larynx, multiple
endocrine neoplasias 2A and 2B (MENS 2A and MENS 2B) (including
RET-mediated MENS), thyroid cancer (including sporadic and familial
medullary thyroid carcinoma), papillary thyroid carcinoma,
parathyroid carcinoma (including any RET-mediated thyroid
carcinoma), follicular thyroid cancer, anaplastic thyroid cancer,
bronchial carcinoid, oat cell carcinoma, lung cancer, small-cell
lung cancer (including FLT3 and/or Kit-mediated small cell lung
cancer), non-small-cell lung cancer, stomach/gastric cancer,
gastrointestinal cancer, gastrointestinal stromal tumors (GIST)
(including Kit-mediated GIST and PDGFR .alpha.-mediated GIST),
colon cancer, colorectal cancer, pancreatic cancer, islet cell
carcinoma, hepatic/liver cancer, metastases to the liver, bladder
cancer, renal cell cancer (including PDGFR-mediated renal cell
cancer), cancers of the genitourinary tract, ovarian cancer
(including Kit-mediated and/or PDGFR-mediated ovarian cancer),
endometrial cancer (including CSF-1R-mediated endometrial cancer),
cervical cancer, breast cancer (including FLT3-mediated and/or
PDGFR-mediated breast cancer), prostate cancer (including
Kit-mediated prostate cancer), germ cell tumors (including
Kit-mediated germ cell tumors), seminomas (including Kit-mediated
seminomas), dysgerminomas (including Kit-mediated dysgerminomas),
melanoma (including PDGFR-mediated melanoma), metastases to the
bone (including CSF-1R-mediated bone metastases), metastatic tumors
(including VEGFR-mediated tumors), stromal tumors, neuroendocrine
tumors, tumor angiogenesis (including VEGFR-mediated tumor
angiogenesis), and mixed mesodermal tumors.
[0275] In certain embodiments, the proliferative disease is
sarcomas, including, but not limited to, PDGFR-mediated sarcomas,
osteosarcoma, osteogenic sarcoma, bone cancer, glioma (including
PDGFR-mediated and/or CSF-1R-mediated glioma), astrocytoma,
vascular tumors (including VEGFR-mediated vascular tumors),
Kaposi's sarcoma, carcinosarcoma, hemangiosarcomas (including
VEGFR3-mediated hemangiosarcomas), and lymphangiosarcoma (including
VEGFR3-mediated lymphangiosarcoma).
[0276] In certain embodiments, the proliferative disease is a
hematologic malignancy. In certain embodiments, the proliferative
disease is a relapsed hematologic malignancy. In certain
embodiments, the proliferative disease is a refractory hematologic
malignancy. In certain embodiments, the proliferative disease is a
drug-resistant hematologic malignancy. In certain embodiments, the
proliferative disease is a multidrug-resistant hematologic
malignancy. In certain embodiments, the proliferative disease is a
Bcr-Abl kinase inhibitor-resistant hematologic malignancy. In
certain embodiments, the proliferative disease is an
imatinib-resistant hematologic malignancy. In certain embodiments,
the proliferative disease is a dasatinib-resistant hematologic
malignancy. In certain embodiments, the proliferative disease is a
nilatinib-resistant hematologic malignancy. In certain embodiments,
the proliferative disease is a bosutinib-resistant hematologic
malignancy. In certain embodiments, the proliferative disease is a
cytarabine-resistant hematologic malignancy.
[0277] In certain embodiments, the hematologic malignancy is
myeloma, leukemia, myeloproliferative diseases, acute myeloid
leukemia (AML) (including FLT3 mediated and/or KIT-mediated and/or
CSF1R-mediated acute myeloid leukemia), chronic myeloid leukemias
(CML) (including FLT3-mediated and/or PDGFR-mediated chronic
myeloid leukemia), myelodysplastic leukemias (including
FLT3-mediated myelodysplastic leukemia), myelodysplastic syndrome
(including FLT3 mediated and/or Kit-mediated myelodysplastic
syndrome), idiopathic hypereosinophilic syndrome (HES) (including
PDGFR-mediated HES), chronic eosinophilic leukemia (CEL) (including
PDGFR-mediated CEL), chronic myelomonocytic leukemia (CMML), mast
cell leukemia (including Kit-mediated mast cell leukemia), or
systemic mastocytosis (including Kit-mediated systemic
mastocytosis).
[0278] In certain embodiments, the hematologic malignancy is
lymphoma, lymphoproliferative diseases, acute lymphoblastic
leukemia (ALL), B-cell acute lymphoblastic leukemias, T-cell acute
lymphoblastic leukemias, chronic lymphocytic leukemia (CLL),
natural killer (NK) cell leukemia, B-cell lymphoma, T-cell
lymphoma, or natural killer (NK) cell lymphoma.
[0279] In an embodiment, the hematologic malignancy is
myelodysplastic syndrome (MDS).
[0280] In certain embodiments, the hematologic malignancy is
Langerhans cell histiocytosis (including CSF-1R-mediated and/or
FLT3-mediated Langerhans cell histiocytosis), mast cell tumors, or
mastocytosis.
[0281] In certain embodiments, the hematologic malignancy is
leukemia. In certain embodiments, the hematologic malignancy is
relapsed leukemia. In certain embodiments, the hematologic
malignancy is refractory leukemia. In certain embodiments, the
hematologic malignancy is drug-resistant leukemia. In certain
embodiments, the hematologic malignancy is multidrug-resistant
leukemia. In certain embodiments, the hematologic malignancy is a
Bcr-Abl kinase inhibitor-resistant leukemia. In certain
embodiments, the hematologic malignancy is imatinib-resistant
leukemia. In certain embodiments, the hematologic malignancy is
dasatinib-resistant leukemia. In certain embodiments, the
hematologic malignancy is nilatinib-resistant leukemia. In certain
embodiments, the hematologic malignancy is bosutinib-resistant
leukemia.
[0282] In certain embodiments, the hematologic malignancy is
cytarabine-resistant leukemia.
[0283] In certain embodiments, the leukemia is acute leukemia. In
certain embodiments, the leukemia is relapsed acute leukemia. In
certain embodiments, the leukemia is refractory acute leukemia. In
certain embodiments, the leukemia is drug-resistant acute leukemia.
In certain embodiments, the leukemia is multidrug-resistant acute
leukemia. In certain embodiments, the leukemia is a Bcr-Abl kinase
inhibitor-resistant acute leukemia. In certain embodiments, the
leukemia is imatinib-resistant acute leukemia. In certain
embodiments, the leukemia is dasatinib-resistant acute leukemia. In
certain embodiments, the leukemia is nilatinib-resistant acute
leukemia. In certain embodiments, the leukemia is
bosutinib-resistant acute leukemia. In certain embodiments, the
leukemia is cytarabine-resistant acute leukemia. In certain
embodiments, the leukemia is a hereditary leukemia. In certain
embodiments, the hereditary leukemia is severe congenital
neutropenia (SCN). In certain embodiments, the hereditary leukemia
is familial platelet disorder with acute myelogenous leukemia
(FDP/AML). In certain embodiments, the leukemia is caused by LEF1.
In certain embodiments, the leukemia is mediated by LEF1. In
certain embodiments, the leukemia is caused by GSK3.
[0284] In certain embodiments, the leukemia is ALL. In certain
embodiments, the leukemia is relapsed ALL. In certain embodiments,
the leukemia is refractory ALL. In certain embodiments, the
leukemia is drug-resistant ALL. In certain embodiments, the
leukemia is multidrug-resistant ALL. In certain embodiments, the
leukemia is a Bcr-Abl kinase inhibitor-resistant ALL. In certain
embodiments, the leukemia is imatinib-resistant ALL. In certain
embodiments, the leukemia is dasatinib-resistant ALL. In certain
embodiments, the leukemia is nilatinib-resistant ALL. In certain
embodiments, the leukemia is bosutinib-resistant ALL. In certain
embodiments, the leukemia is cytarabine-resistant ALL.
[0285] In one embodiment, ALL is leukemia that originates in the
blast cells of the bone marrow (B-cells), thymus (T-cells), or
lymph nodes. ALL is categorized according to the
French-American-British (FAB) Morphological Classification Scheme
as L1--mature-appearing lymphoblasts (T-cells or pre-B-cells),
L2--immature and pleomorphic (variously shaped) lymphoblasts
(T-cells or pre-B-cells), and L3--lymphoblasts (B-cells; Burkitt's
cells). In another embodiment, ALL originates in the blast cells of
the bone marrow (B-cells). In yet another embodiment, ALL
originates in the thymus (T-cells). In yet another embodiment, ALL
originates in the lymph nodes. In yet another embodiment, ALL is L1
type characterized by mature-appearing lymphoblasts (T-cells or
pre-B-cells). In yet another embodiment, ALL is L2 type
characterized by immature and pleomorphic (variously shaped)
lymphoblasts (T-cells or pre-B-cells). In still another embodiment,
ALL is L3 type characterized by lymphoblasts (B-cells; Burkitt's
cells).
[0286] In certain embodiments, the leukemia is AML. In certain
embodiments, the leukemia is relapsed AML. In certain embodiments,
the leukemia is refractory AML. In certain embodiments, the
leukemia is drug-resistant AML. In certain embodiments, the
leukemia is multidrug-resistant AML. In certain embodiments, the
leukemia is a Bcr-Abl kinase inhibitor-resistant AML. In certain
embodiments, the leukemia is imatinib-resistant AML. In certain
embodiments, the leukemia is dasatinib-resistant AML. In certain
embodiments, the leukemia is nilatinib-resistant AML. In certain
embodiments, the leukemia is bosutinib-resistant AML. In certain
embodiments, the leukemia is cytarabine-resistant AML. In certain
embodiments, AML has a RAS mutation. In certain embodiments, the
RAS mutation is NRAS, KRAS, or HRAS. In certain embodiments, the
RAS mutation is NRAS. In certain embodiments, the RAS mutation is
KRAS. In certain embodiments, the RAS mutation is HRAS.
[0287] In certain embodiments, AML is undifferentiated AML (M0),
myeloblastic leukemia (M1), myeloblastic leukemia (M2),
promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic
leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic
leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia
(M7). In one embodiment, AML is undifferentiated AML (M0). In
another embodiment, AML is myeloblastic leukemia (M1). In yet
another embodiment, AML is myeloblastic leukemia (M2). In yet
another embodiment, AML is promyelocytic leukemia (M3 or M3 variant
[M3V]). In yet another embodiment, AML is myelomonocytic leukemia
(M4 or M4 variant with eosinophilia [M4E]). In yet another
embodiment, AML is monocytic leukemia (M5). In yet another
embodiment, AML is erythroleukemia (M6). In still another
embodiment, AML is megakaryoblastic leukemia (M7). In certain
embodiments, the leukemia is chronic leukemia. In certain
embodiments, the leukemia is relapsed chronic leukemia. In certain
embodiments, the leukemia is refractory chronic leukemia. In
certain embodiments, the leukemia is drug-resistant chronic
leukemia. In certain embodiments, the leukemia is
multidrug-resistant chronic leukemia. In certain embodiments, the
leukemia is a Bcr-Abl kinase inhibitor-resistant chronic leukemia.
In certain embodiments, the leukemia is imatinib-resistant chronic
leukemia. In certain embodiments, the leukemia is
dasatinib-resistant chronic leukemia. In certain embodiments, the
leukemia is nilatinib-resistant chronic leukemia. In certain
embodiments, the leukemia is bosutinib-resistant chronic leukemia.
In certain embodiments, the leukemia is cytarabine-resistant
chronic leukemia.
[0288] In certain embodiments, the leukemia is CLL. In certain
embodiments, the leukemia is relapsed CLL. In certain embodiments,
the leukemia is refractory CLL. In certain embodiments, the
leukemia is drug-resistant CLL. In certain embodiments, the
leukemia is multidrug-resistant CLL. In certain embodiments, the
leukemia is a Bcr-Abl kinase inhibitor-resistant CLL. In certain
embodiments, the leukemia is imatinib-resistant CLL. In certain
embodiments, the leukemia is dasatinib-resistant CLL. In certain
embodiments, the leukemia is nilatinib-resistant CLL. In certain
embodiments, the leukemia is bosutinib-resistant CLL. In certain
embodiments, the leukemia is cytarabine-resistant CLL.
[0289] In certain embodiments, the leukemia is CML. In certain
embodiments, the leukemia is relapsed CML. In certain embodiments,
the leukemia is refractory CML. In certain embodiments, the
leukemia is drug-resistant CML. In certain embodiments, the
leukemia is multidrug-resistant CML. In certain embodiments, the
leukemia is a Bcr-Abl kinase inhibitor-resistant CML. In certain
embodiments, the leukemia is imatinib-resistant CML. In certain
embodiments, the leukemia is dasatinib-resistant CML. In certain
embodiments, the leukemia is nilatinib-resistant CML. In certain
embodiments, the leukemia is bosutinib-resistant CML. In certain
embodiments, the leukemia is cytarabine-resistant CML. In certain
embodiments, the leukemia is juvenile CML. In certain embodiments,
the leukemia is juvenile CML with one or more NF-1 mutations.
[0290] In certain embodiments, the leukemia is T-cell leukemia. In
one embodiment, the T-cell leukemia is peripheral T-cell leukemia,
T-cell lymphoblastic leukemia, cutaneous T-cell leukemia, and adult
T-cell leukemia. In another embodiment, the T-cell leukemia is
peripheral T-cell leukemia. In yet another embodiment, the T-cell
leukemia is T-cell lymphoblastic leukemia. In yet another
embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In
still another embodiment, the T-cell leukemia is adult T-cell
leukemia.
[0291] In certain embodiments, the leukemia is Philadelphia
positive. In one embodiment, the Philadelphia positive leukemia is
Philadelphia positive AML, including, but not limited to,
undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic
leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]),
myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]),
monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic
leukemia (M7). In another embodiment, the Philadelphia positive
leukemia is Philadelphia positive ALL.
[0292] In certain embodiments, the proliferative disease is cancer,
including, but not limited to, head and neck cancer (originating
lip, oral cavity, oropharynx, hypopharynx, larynx, nasopharynx,
nasal cavity, paranasal sinuses, or salivary glands), lung cancer
(including small cell lung cancer and non-small cell lung cancer),
gastrointestinal tract cancers (including esophageal cancer),
gastric cancer, colorectal cancer, anal cancer, pancreatic cancer,
liver cancer, gallbladder cancer, extrahepatic bile duct cancer,
cancer of the ampulla of vater, breast cancer, gynecologic cancers
(including cancer of uterine cervix), cancer of the uterine body,
vaginal cancer, vulvar cancer, ovarian cancer, gestational
trophoblastic cancer neoplasia, testicular cancer, urinary tract
cancers (including renal cancer), urinary bladder cancer, prostate
cancer, penile cancer, urethral cancer, neurologic tumors,
endocrine neoplasms (including carcinoid and islet cell tumors),
pheochromocytoma, adrenal cortical carcinoma, parathyroid
carcinoma, and metastases to endocrine glands.
[0293] Further examples of cancers are basal cell carcinoma,
squamous cell carcinoma, chondrosarcoma (a cancer arising in
cartilage cells), mesenchymal-chondrosarcoma, soft tissue sarcomas
(including malignant tumors that may arise in any of the mesodermal
tissues (muscles, tendons, vessels that carry blood or lymph,
joints and fat)), soft tissue sarcomas (include alveolar soft-part
sarcoma), angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma,
malignant fibrous histiocytoma, hemangiopericytoma, mesenchymoma,
schwannoma, peripheral neuroectodermal tumours, rhabdomyosarcoma,
synovial sarcoma, gestational trophoblastic tumor (malignancy in
which the tissues formed in the uterus following conception become
cancerous), Hodgkin's lymphoma, and laryngeal cancer.
[0294] In certain embodiments, the proliferative disease is a
nonmalignant proliferation disease, including, but not limited to,
atherosclerosis (including PDGFR-mediated atherosclerosis),
restenosis following vascular angioplasty (including PDGFR-mediated
restenosis), and fibroproliferative disorders (including
obliterative bronchiolitis and idiopathic myelofibrosis).
[0295] In certain embodiments, the proliferative disease is an
inflammatory disease or disorder related to immune dysfunction,
immunodeficiency, or immunomodulation, including, but not limited
to, autoimmune diseases, tissue transplant rejection,
graft-versus-host disease, wound healing, kidney disease, multiple
sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergic
rhinitis, inflammatory bowel diseases (including Crohn's disease
and ulcerative colitis (UC)), systemic lupus erythematosis (SLE),
arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis,
asthma, and chronic obstructive pulmonary disease (COPD).
[0296] In certain embodiments, the proliferative disease is an
infectious disease. In certain embodiments, the infectious disease
is fungal infection. In certain embodiments, the infectious disease
is a superficial mycose (e.g., Tinea versicolor). In certain
embodiments, the infectious disease is a cutaneous mycose (e.g.,
epidermis). In certain embodiments, the infectious disease is a
subcutaneous mycose. In certain embodiments, the infectious disease
is a systemic mycose.
[0297] In certain embodiments, the proliferative disease is
leukemia, adult T-cell leukemia, promyelocytic leukemia, pre-B cell
leukemia, lymphoma, Mantle cell lymphoma, breast cancer, pancreatic
cancer, prostate cancer, head and neck cancer, ovarian cancer,
melanoma, giloma, liver cancer, renal cancer, colorectal cancer,
rhabdomyosarcoma, tongue cancer, stomach cancer, multiple myeloma,
bladder cancer, thyroid cancer, epidermoid carcinoma, lung cancer,
NSC lung cancer, or large cell lung cancer.
[0298] In certain embodiments, the proliferative disease is adult
T-cell leukemia, promyelocytic leukemia, pre-B cell leukemia,
lymphoma, mantle cell lymphoma, pancreatic cancer, prostate cancer,
head and neck cancer, ovarian cancer, melanoma, giloma, liver
cancer, renal cancer, colorectal cancer, rhabdomyosarcoma, tongue
cancer, stomach cancer, multiple myeloma, bladder cancer, thyroid
cancer, epidermoid carcinoma, NSC lung cancer, or large cell lung
cancer.
[0299] In certain embodiments, the proliferative disease is
leukemia, adult T-cell leukemia, promyelocytic leukemia, pre-B cell
leukemia, lymphoma, mantle cell lymphoma, breast cancer, head and
neck cancer, ovarian cancer, colorectal cancer, tongue cancer,
multiple myeloma, or large cell lung cancer.
[0300] Also provided are compounds described herein for use in the
treatments described herein.
[0301] Also provided are uses of compounds described herein for the
manufacture of medicaments for the treatments described herein.
[0302] Assay Methods
[0303] Patient samples were obtained from a non-interventional and
prospective study. The study included samples from adult patients
over 18 years of age who were diagnosed with Acute Myeloid Leukemia
(AML).
[0304] In one embodiment, the method of data acquisition was
performed as follows: on day 1 bone marrow (BM) or peripheral blood
(PB) patient sample was received. A small part was separated from
the rest of the sample for validation, while the majority of the
sample was diluted with culture media and plated into 96-well
plates previously prepared with the desired compounds and compound
combinations, e.g., a compound or compound combination described
herein. The number of live leukemic cells seeded in each well was
fixed between 8000 and 32000, depending on the percentage of
leukemic cells for each sample. These plates were incubated for 72
hours and analyzed on day 4. Antibodies were added to identify
leukemic cells using a gating strategy based on FSC/SSC and
expression or lack of expression of different surface markers. The
monoclonal antibodies selection was performed to optimize the
identification of leukemic cell in each sample.
[0305] In one embodiment, non-limiting examples of biomarkers such
as the biomarkers CD34, CD45, CD117, and HLADR known as "backbone
markers" for AML (van Dongen, J. J. and A. Orfao, EuroFlow:
Resetting leukemia and lymphoma immunophenotyping. Basis for
companion diagnostics and personalized medicine, Leukemia, 2012,
26, 1899-907) were included in the combination.
[0306] In one embodiment, antibody combinations such as CD117/CD45,
CD34/CD45, and HLADR/CD45 were used. Live leukemic cells were
identified by their light scatter properties
(FSC.sup.int/hi/SSC.sup.int) in the absence of Annexin-V-FITC
staining. FSC/SSC selection was performed to exclude debris. The
average percentage of cell viability upon receipt of the sample was
80% and samples were only processed if the viability was greater
than 50%.
[0307] In one embodiment, sample validation was performed as
follows: BM and PB samples were extracted under sterile conditions
and received in the laboratory within 24 hours of extraction.
Initial analysis evaluated the number of pathological cells and
their viability. Different volumes of sample (1 .mu.L, 3 .mu.L, 5
.mu.L and 7 .mu.L) were aliquoted in duplicate into a 96-well
plate. To lyse red blood cells, 180 .mu.L of ammonium chloride
lysis solution was added to each well (2 g KHCO.sub.3, 16.58 g
NH.sub.4Cl, 0.074 g Na.sub.2EDTA..sub.2H.sub.2O, H.sub.2O to 1 L).
Following a 10 min incubation period at 4.degree. C., plate was
centrifuged for 5 min at 1200 rpm and the supernatant removed. The
lysis step was performed twice. To analyze, 20 .mu.L of a
combination of Annexin V-FITC (Immunostep, Salamanca, Spain),
binding buffer (BB, 2.4 g HEPES, 8.19 g NaCl, 0.37 g Cl.sub.2Ca,
H.sub.2O to 1 L), and the following monoclonal antibodies (mAb)
were added to each well: CD117 (clone 104D2)-PE (Becton Dickinson,
San Jose, Calif., US), CD34 (clone 581)-PerCP (BioLegend, San
Diego, Calif., US), HLADR (clone L243)-PB (BioLegend) and CD45
(HI30)-PO (Life Technologies, Carlsbad, Calif., US) (van Dongen, J.
J., et al., EuroFlow antibody panels for standardized n-dimensional
flow cytometric immunophenotyping of normal, reactive and malignant
leukocytes, Leukemia, 2012, 26, 1908-75). After 15 min of
incubation at room temperature in the dark, a wash step was
performed using binding buffer solution. The pellet was resuspended
in 30 .mu.L BB for analysis in Vivia's ExviTech.COPYRGT. platform.
Cell count and viability upon arrival were computed and the optimal
volume of sample to use per well was determined.
[0308] In one embodiment, the assay was performed according to
following method: the whole sample was diluted with RPMI 1640,
supplemented with 20% (v/v) FBS (Thermo Scientific, Waltham, Mass.,
US), 2% HEPES, 1% antibiotic (Zell Shield, Labclinics, Barcelona,
Spain) and 1% L-glutamine 200 mM (Lonza, Hopkinton, Mass., US) to a
final volume of 60 .mu.L per well. The mixture was dispensed into
96-well plates containing a compound described herein with a
Multidrop Combi Smart (Thermo Scientific, Waltham, Mass., US). Drug
plates were previously prepared using an Echo 550 Liquid Handler
(LabCyte, Sunnyvale, Calif., US). Five or eight concentrations were
used for each compound tested, adjusted to cover the range of
activities across patients. The compounds tested were also tested
against the corresponding parent as a control. The plates were
incubated for 48 hours at 37.degree. C. in humidified air
containing 5% CO.sub.2.
[0309] In one embodiment, data analysis was conducted with Summit
software (Beckman Coulter). Identification of pathological cells
was performed using a gating strategy based on FSC/SSC and
expression or lack of expression of the different mAb markers.
Depletion was measured as the difference in the number of live
cells in a well with the compounds described herein vs the control
wells without the compounds. Annexin V was then used to exclude
dying cells and measure only the number of live cells in the drug
wells and in the control wells. Those cells without Annexin V
staining and appropriate FSC/SSC were considered as live cells
(Koopman, G., et al., Annexin V for flow cytometric detection of
phosphatidylserine expression on B cells undergoing apoptosis,
Blood, 1994, 84, 1415-20). Using the above parameters, FCS Analyzer
was used to determine the effect of each of the individual
compound. Data were transferred to ActivityBase (IDBS, Guildford,
UK) for final analysis.
[0310] Compounds can be assayed for liver cancer activity according
to any assay known to those of skill in the art.
[0311] Further, compounds can be assayed for accumulation in liver
cells of a subject according to any assay known to those of skill
in the art. In certain embodiments, a compound can be administered
to the subject, and a liver cell of the subject can be assayed for
the compound or a derivative thereof, e.g. a nucleoside, nucleoside
phosphate or nucleoside triphosphate derivative thereof.
[0312] In certain embodiments, a nucleoside compound is
administered to cells, such as liver cells, in vivo or in vitro,
and the nucleoside triphosphate levels delivered intracellularly
are measured, to indicate delivery of the compound and
triphosphorylation in the cell. The levels of intracellular
nucleoside triphosphate can be measured using analytical techniques
known in the art. Methods of detecting ddATP are described herein
below by way of example, but other nucleoside triphosphates can be
readily detected using the appropriate controls, calibration
samples and assay techniques.
[0313] In certain embodiments, ddATP concentrations are measured in
a sample by comparison to calibration standards made from control
samples. The ddATP concentrations in a sample can be measured using
an analytical method such as HPLC LC MS. In certain embodiments, a
test sample is compared to a calibration curve created with known
concentrations of ddATP to thereby obtain the concentration of that
sample.
[0314] In certain embodiments, the samples are manipulated to
remove impurities such as salts (Na.sup.+, K.sup.+, etc.) before
analysis. In certain embodiments, the lower limit of quantitation
is about .about.0.2 pmol/mL for hepatocyte cellular extracts
particularly where reduced salt is present.
[0315] In certain embodiments, the method allows successfully
measuring triphosphate nucleotides formed at levels of 1-10,000
pmol per million cells in e.g. cultured hepatocytes and HepG2
cells
[0316] Combination with Other Therapeutic Agents
[0317] In one embodiment is a combination comprising a compounds as
described herein, e.g., of Formulas I-VIII, or pharmaceutically
acceptable salt thereof, and one, two, three or more other
therapeutic agents, e.g. anti-cancer agents.
[0318] In certain embodiments, the compounds and compositions
provided herein are useful in methods of treatment of a cancer,
that comprise further administration of a second agent effective
for the treatment of the cancer in a subject in need thereof. The
second agent can be any agent known to those of skill in the art to
be effective for the treatment of the cancer, including those
currently approved by the FDA. In certain embodiments, the cancer
is selected from liver cancer, breast cancer, ovarian cancer, lung
cancer, pancreatic cancer or leukemic cancer. In an embodiment the
cancer is liver cancer.
[0319] In certain embodiments, a compound provided herein is
administered in combination with one second agent. In further
embodiments, a compound provided herein is administered in
combination with two second agents. In still further embodiments, a
compound provided herein is administered in combination with two or
more second agents.
[0320] As used herein, the term "in combination" includes the use
of more than one therapy (e.g., one or more prophylactic and/or
therapeutic agents). The use of the term "in combination" does not
restrict the order in which therapies (e.g., prophylactic and/or
therapeutic agents) are administered to a subject with a disorder.
A first therapy (e.g., a prophylactic or therapeutic agent such as
a compound provided herein) can be administered prior to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4
hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1
week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12
weeks before), concomitantly with, or subsequent to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4
hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1
week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12
weeks after) the administration of a second therapy (e.g., a
prophylactic or therapeutic agent) to a subject with a
disorder.
[0321] As used herein, the term "synergistic" includes a
combination of a compound provided herein and another therapy
(e.g., a prophylactic or therapeutic agent) which has been or is
currently being used to prevent, manage or treat a disorder, which
is more effective than the additive effects of the therapies. A
synergistic effect of a combination of therapies (e.g., a
combination of prophylactic or therapeutic agents) permits the use
of lower dosages of one or more of the therapies and/or less
frequent administration of said therapies to a subject with a
disorder. The ability to utilize lower dosages of a therapy (e.g.,
a prophylactic or therapeutic agent) and/or to administer said
therapy less frequently reduces the toxicity associated with the
administration of said therapy to a subject without reducing the
efficacy of said therapy in the prevention or treatment of a
disorder). In addition, a synergistic effect can result in improved
efficacy of agents in the prevention or treatment of a disorder.
Finally, a synergistic effect of a combination of therapies (e.g.,
a combination of prophylactic or therapeutic agents) may avoid or
reduce adverse or unwanted side effects associated with the use of
either therapy alone.
[0322] The active compounds provided herein can be administered in
combination or alternation with another therapeutic agent, in
particular an anti-cancer agent. In combination therapy, effective
dosages of two or more agents are administered together, whereas in
alternation or sequential-step therapy, an effective dosage of each
agent is administered serially or sequentially. The dosages given
will depend on absorption, inactivation and excretion rates of the
drug as well as other factors known to those of skill in the art.
It is to be noted that dosage values will also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens and schedules should be adjusted over time according to
the individual need and the professional judgment of the person
administering or supervising the administration of the
compositions.
[0323] In certain embodiments, the second agent is selected from
the group consisting of sorafenib tosylate (Nexavar), radiation
therapy, selective internal radiation therapy (e.g., SIR-Spheres
and TheraSphere), ethiodized oil (Lipidol), pexastimogene
devacirepvec (Pexa-Vec, JX-594, Jennarex), Quinacrine (Clevelane
BioLabs), CC-223 (Celgene), CF102 (Can-Fite), SGI-110 (Astex), and
G-202 (Genspera).
[0324] In one embodiment, the other anticancer agent is selected
from the group consisting of vascular endothelial growth factor
(VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen
inhibitors, alkylating agents, anti-tumor antibiotics,
anti-metabolites, retinoids, immunomodulatory agents including but
not limited to anti-cancer vaccines, CTLA-4, LAG-3, PD-1
antagonists and BET bromodomain inhibitors.
[0325] Examples of vascular endothelial growth factor (VEGF)
receptor inhibitors include, but are not limited to, bevacizumab
(sold under the trademark AVASTIN by Genentech/Roche), axitinib,
(N-methyl-2-[[3-[([pound])-2-pyridin-2-ylethenyl]-1
H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and
described in PCT Publication No. WO 01/002369), Brivanib Alaninate
((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f-
][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known
as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1
H-indoi-6-y!)-2-[(4-pyridinyimethyj)amino]-3-pyfidinecarboxamide.
and described in PCT Publication No. WO 02/068470), pasireotide
(also known as SO 230, and described in PCT Publication No. WO
02/010192), and sorafenib (sold under the tradename NEXAVAR).
[0326] Examples of topoisomerase II inhibitors, include but are not
limited to, etoposide (also known as VP-16 and Etoposide phosphate,
sold under the tradenames TOPOSAR, VEPESID and ETOPOPHOS), and
teniposide (also known as VM-26, sold under the tradename
VUMON).
[0327] Examples of alkylating agents, include but are not limited
to, 5-azacytidine (sold under the trade name VIDAZA), decitabine
(sold under the trade name of DECOGEN), temozolomide (sold under
the trade names TEMODAR and TEMODAL by Schering-Plough/Merck),
dactinomycin (also known as actinomycin-D and sold under the
tradename COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin,
and phenylalanine mustard, sold under the tradename ALKERAN),
altretamine (also known as hexamethylmelamine (HMM), sold under the
tradename HEXALEN), carmustine (sold under the tradename BCNU),
bendamustine (sold under the tradename TREANDA), busulfan (sold
under the tradenames Busulfex.RTM. and Myleran.RTM.), carboplatin
(sold under the tradename Paraplatin.RTM.), lomustine (also known
as CCNU, sold under the tradename CeeNU.RTM.), cisplatin (also
known as CDDP, sold under the tradenames Platinol.RTM. and
Platinol.RTM.-AQ), chlorambucil (sold under the tradename
Leukeran.RTM.), cyclophosphamide (sold under the tradenames
Cytoxan.RTM. and Neosar.RTM.), dacarbazine (also known as DTIC, DIC
and imidazole carboxamide, sold under the tradename
DTIC-Dome.RTM.), altretamine (also known as hexamethylmelamine
(HMM) sold under the tradename Hexalen.RTM.), ifosfamide (sold
under the tradename Ifex.RTM.), procarbazine (sold under the
tradename Matulane.RTM.), mechlorethamine (also known as nitrogen
mustard, mustine and mechloroethamine hydrochloride, sold under the
tradename Mustargen.RTM.), streptozocin (sold under the tradename
Zanosar.RTM.), thiotepa (also known as thiophosphoamide, TESPA and
TSPA, and sold under the tradename Thioplex.RTM..
[0328] Examples of anti-tumor antibiotics include, but are not
limited to, doxorubicin (sold under the tradenames Adriamycin.RTM.
and Rubex.RTM.), bleomycin (sold under the tradename
lenoxane.RTM.), daunorubicin (also known as dauorubicin
hydrochloride, daunomycin, and rubidomycin hydrochloride, sold
under the tradename Cerubidine.RTM.), daunorubicin liposomal
(daunorubicin citrate liposome, sold under the tradename
DaunoXome.RTM.), mitoxantrone (also known as DHAD, sold under the
tradename Novantrone.RTM.), epirubicin (sold under the tradename
Ellence.TM.), idarubicin (sold under the tradenames Idamycin.RTM.,
Idamycin PFS.RTM.), and mitomycin C (sold under the tradename
Mutamycin.RTM.).
[0329] Examples of anti-metabolites include, but are not limited
to, claribine (2-chlorodeoxyadenosine, sold under the tradename
leustatin.RTM.), 5-fluorouracil (sold under the tradename
Adrucil.RTM.), 6-thioguanine (sold under the tradename
Purinethol.RTM.), pemetrexed (sold under the tradename
Alimta.RTM.), cytarabine (also known as arabinosylcytosine (Ara-C),
sold under the tradename Cytosar-U.RTM.), cytarabine liposomal
(also known as Liposomal Ara-C, sold under the tradename
DepoCyt.TM.), decitabine (sold under the tradename Dacogen.RTM.),
hydroxyurea (sold under the tradenames Hydrea.RTM., Droxia.TM. and
Mylocel.TM.), fludarabine (sold under the tradename Fludara.RTM.),
floxuridine (sold under the tradename FUDR.RTM.), cladribine (also
known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename
Leustatin.TM.), methotrexate (also known as amethopterin,
methotrexate sodium (MTX), sold under the tradenames
Rheumatrex.RTM. and Trexall.TM.), and pentostatin (sold under the
tradename Nipent.RTM.).
[0330] Examples of retinoids include, but are not limited to,
alitretinoin (sold under the tradename Panretin.RTM.), tretinoin
(all-trans retinoic acid, also known as ATRA, sold under the
tradename Vesanoid.RTM.), Isotretinoin (13-c/s-retinoic acid, sold
under the tradenames Accutane.RTM., Amnesteem.RTM., Claravis.RTM.,
Clarus.RTM., Decutan.RTM., Isotane.RTM., Izotech.RTM.,
Oratane.RTM., Isotret.RTM., and Sotret.RTM.), and bexarotene (sold
under the tradename Targretin.RTM.).
[0331] "PD-1 antagonist" means any chemical compound or biological
molecule that blocks binding of PD-L1 expressed on a cancer cell to
PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and
preferably also blocks binding of PD-L2 expressed on a cancer cell
to the immune-cell expressed PD-1. Alternative names or synonyms
for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for
PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and
PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the
treatment method, medicaments and uses of the present invention in
which a human individual is being treated, the PD-1 antagonist
blocks binding of human PD-L1 to human PD-1, and preferably blocks
binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1
amino acid sequences can be found in NCBI Locus No.: NP_005009.
Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI
Locus No.: NP_054862 and NP_079515, respectively.
[0332] PD-1 antagonists useful in any of the treatment method,
medicaments and uses of the present invention include a monoclonal
antibody (mAb), or antigen binding fragment thereof, which
specifically binds to PD-1 or PD-L1, and preferably specifically
binds to human PD-1 or human PD-L1. The mAb may be a human
antibody, a humanized antibody or a chimeric antibody, and may
include a human constant region. In some embodiments the human
constant region is selected from the group consisting of IgG1,
IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments,
the human constant region is an IgG1 or IgG4 constant region. In
some embodiments, the antigen binding fragment is selected from the
group consisting of Fab, Fab'-SH, F(ab').sub.2, scFv and Fv
fragments.
[0333] Examples of mAbs that bind to human PD-1, and useful in the
treatment method, medicaments and uses of the present invention,
are described in U.S. Pat. No. 7,488,802, U.S. Pat. No. 7,521,051,
U.S. Pat. No. 8,008,449, U.S. Pat. No. 8,354,509, U.S. Pat. No.
8,168,757, WO2004/004771, WO2004/072286, WO2004/056875, and
US2011/0271358.
[0334] Examples of mAbs that bind to human PD-L1, and useful in the
treatment method, medicaments and uses of the present invention,
are described in WO2013/019906, WO2010/077634 A1 and U.S. Pat. No.
8,383,796. Specific anti-human PD-L1 mAbs useful as the PD-1
antagonist in the treatment method, medicaments and uses of the
present invention include MPDL3280A, BMS-936559, MEDI4736,
MSB0010718C and an antibody which comprises the heavy chain and
light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21,
respectively, of WO2013/019906.
[0335] Other PD-1 antagonists useful in any of the treatment
method, medicaments and uses of the present invention include an
immunoadhesin that specifically binds to PD-1 or PD-L1, and
preferably specifically binds to human PD-1 or human PD-L1, e.g., a
fusion protein containing the extracellular or PD-1 binding portion
of PD-L1 or PD-L2 fused to a constant region such as an Fc region
of an immunoglobulin molecule. Examples of immunoadhesion molecules
that specifically bind to PD-1 are described in WO2010/027827 and
WO2011/066342. Specific fusion proteins useful as the PD-1
antagonist in the treatment method, medicaments and uses of the
present invention include AMP-224 (also known as B7-DCIg), which is
a PD-L2-FC fusion protein and binds to human PD-1.
[0336] Examples of other cytotoxic agents include, but are not
limited to, arsenic trioxide (sold under the tradename
Trisenox.RTM.), asparaginase (also known as L-asparaginase, and
Erwinia L-asparaginase, sold under the tradenames Elspar.RTM. and
Kidrolase.RTM.).
[0337] In an embodiment, the other anticancer agent is a BET
bromodomain inhibitor. Examples of BET bromodomain inhibitor
include the compounds described in U.S. Pat. No. 5,712,274,
WO1994006802, U.S. Pat. No. 8,476,260 and WO2009/084693.
EXAMPLES
[0338] As used herein, the symbols and conventions used in these
processes, schemes and examples, regardless of whether a particular
abbreviation is specifically defined, are consistent with those
used in the contemporary scientific literature, for example, the
Journal of the American Chemical Society or the Journal of
Biological Chemistry. Specifically, but without limitation, the
following abbreviations may be used in the examples and throughout
the specification: g (grams); mg (milligrams); mL (milliliters);
.mu.L (microliters); mM (millimolar); .mu.M (micromolar); Hz
(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min
(minutes); MS (mass spectrometry); ESI (electrospray ionization);
TLC (thin layer chromatography); HPLC (high pressure liquid
chromatography); THF (tetrahydrofuran); CDCl.sub.3 (deuterated
chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO
(dimethylsulfoxide); DMSO-d.sub.6 (deuterated dimethylsulfoxide);
EtOAc (ethyl acetate); MeOH (methanol); BOC (t-butyloxycarbonyl);
DMTr (4,4'-dimethoxytrityl); and MMTr (dimethoxytrityl).
[0339] For all of the following examples, standard work-up and
purification methods known to those skilled in the art can be
utilized. Unless otherwise indicated, all temperatures are
expressed in .degree. C. (degrees Centigrade). All reactions are
conducted at room temperature unless otherwise noted. Synthetic
methodologies illustrated herein are intended to exemplify the
applicable chemistry through the use of specific examples and are
not indicative of the scope of the disclosure.
##STR00036##
[0340] Reagents B1-B6 were synthesized according to scheme 1 and to
the following general procedure A.
[0341] Procedure A
[0342] To a stirred solution of 4-nitrophenyl phosphorodichloridate
(12.03 mmol) in DCM (5 mL/mmol) was added a solution of
corresponding alcohol (12.03 mmol). The reaction mixture was
stirred at -78.degree. C. and triethylamine (13.23 mmol) was added
at -78.degree. C. over a period of 10 min. The reaction mixture was
stirred at -78.degree. C. for 30 min. A solution of corresponding
amine (12.03 mmol) in DCM (2 mL/mmol) was then added at 0.degree.
C., followed by triethylamine (25.26 mmol) over a period of 15 min.
The reaction mixture was stirred at 0.degree. C. for 1 hour and at
room temperature for 1 hour, and then concentrated under reduced
pressure. The crude residue was treated with ethyl acetate and the
resulting solid was filtered off. The filtrate was concentrated
under reduced pressure. The crude compound was purified by flash
chromatography on silica gel (PE/ethyl acetate: 5 to 40%) to afford
the expected compound.
[0343] Reagent B1: Isopropyl
(2S)-2-[[(4-nitrophenoxy)-phenoxy-phosphoryl]amino]propanoate: MS
(ESI) m/z=409 (MH.sup.+).
[0344] Reagent B2: Ethyl
(2S)-2-[[(2-ethoxy-2-oxo-ethoxy)-(4-nitrophenoxy)phosphoryl]amino]-4-meth-
yl-pentanoate: MS (ESI) m/z=447.1 (MH.sup.+).
[0345] Reagent B3:
N-[(5-nitro-2-furyl)methoxy-(4-nitrophenoxy)phosphoryl]-1-phenyl-methanam-
ine: MS (ESI) m/z=432.2 (MH.sup.-).
[0346] Reagent B4: Methyl
(2S)-2-[[(2-methoxy-2-oxo-ethoxy)-(4-nitrophenoxy)phosphoryl]amino]-4-met-
hyl-pentanoate: MS (ESI) m/z=419.0 (MH.sup.-).
[0347] Reagent B5:
N-[2-(tert-butyldisulfanyl)ethoxy-(4-nitrophenoxy)phosphoryl]-1-phenyl-me-
thanamine: MS (ESI) m/z=457.2 (MH.sup.+).
[0348] Reagent B6:
N-[(3-methyl-2-nitro-imidazol-4-yl)methoxy-(4-nitrophenoxy)phosphoryl]-1--
phenyl-methanamine: MS (ESI) m/z=448.0 (MH.sup.+).
##STR00037##
[0349] Compounds 101b, 102b, 103, 104b, 105 and 106 were
synthesized according to scheme 2 and to the following general
procedure B.
[0350] Procedure B
[0351] To a solution of compound A1 (37.8 mmol) in Pyridine (7
mL/mmol) was added chlorotrimethylsilane (226.8 mmol) at 0.degree.
C. The reaction mixture was stirred at room temperature for 1 hour
and then, 4-dimethylaminopyridine (37.8 mmol) and
4,4'-dimethoxytritylchloride (56.7 mmol) were added at room
temperature. The reaction mixture was stirred at 50.degree. C.
overnight and then, cooled to room temperature. A solution of
saturated aqueous NaHCO.sub.3 was added and the reaction mixture
was extracted twice with DCM. The combined organic layers were
dried, concentrated under reduced pressure and coevaporated with
toluene to afford the expected crude intermediate. To a stirred
solution of this intermediate in methanol (10 mL/mmol) was added
ammonium fluoride (189.0 mmol) at room temperature. The reaction
mixture was stirred overnight at room temperature, then for 2 h 30
at 70.degree. C. and then cooled to room temperature and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography on silica gel (DCM/CH.sub.3OH) to afford
the expected compound.
[0352] To a solution of compound A2 (1.78 mmol) in THF (10 mL/mmol)
at 0.degree. C. was added a solution of tert-butylmagnesium
chloride, 1M in THF (3.73 mmol). The reaction mixture was stirred
at room temperature for 1 hour, and then cooled down to 0.degree.
C. The appropriate reagent B1-6 (1.95 mmol) in THF (10 mL/mmol) was
added, and the reaction mixture was stirred at 0.degree. C. for 1
hour and overnight at room temperature. The reaction mixture was
diluted with ethyl acetate and washed with a saturated solution of
NH.sub.4Cl, water and brine. The combined organic layers were
dried, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica (DCM/ethanol
or DCM/methanol) to afford the expected intermediate;
[0353] To a solution of this intermediate (0.48 mmol) in DCM (15
mL/mmol) was added trifluoroacetic acid (0.8 mL/mmol or 7.2 mmol)
under nitrogen. The reaction mixture was stirred at room
temperature for 2 hours. The reaction was monitored by LC/MS. The
reaction mixture was concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica (DCM/ethanol
or DCM/methanol: 0 to 20%) followed in some cases by RP-18
chromatography (H.sub.2O/CH.sub.3CN) to afford the expected
compound as solid as mixture of diastereoisomers. This mixture was
purified by MS-preparative HPLC or by chirale HPLC to afford the 2
expected diastereoisomers as pure solid compounds.
Example 1
Compound 101b
Isopropyl
(2S)-2-[[[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dih-
ydroxy-tetrahydrothiophen-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
##STR00038##
[0355] Compound 101b was synthesized according to Scheme 2 and to
general procedure B with reagent B1.
[0356] Compound 101b (diastereoisomer 1): white solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm)
[0357] 7.90 (d, J=7.55 Hz, 1H), 7.39-7.35 (m, 2H), 7.20-7.16 (m,
4H), 7.08 (brs, 1H), 6.45 (d, J=4.95 Hz, 1H), 6.00 (dd, J=12.87 Hz
and 10.02 Hz, 1H), 5.81 (brs, 1H), 5.69 (d, J=7.55 Hz, 1H), 5.63
(brs, 1H), 4.86 (heptuplet, J=6.31 Hz, 1H), 4.47-4.41 (m, 1H),
4.26-4.20 (m, 1H), 4.10-4.08 (m, 1H), 4.02-4.00 (m, 1H), 3.82-3.72
(m, 1H), 3.45-3.40 (m, 1H), 1.21 (d, J=7.05 Hz, 3H), 1.165 (d,
J=6.31 Hz, 3H), 1.16 (d, J=6.31 Hz, 3H); .sup.31P NMR
(DMSO-d.sub.6, 162 MHz) .delta. (ppm) 3.28 (s, 1P); MS (ESI)
m/z=529.0 (MH.sup.+).
[0358] Compound 101b (diastereoisomer 2): white solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.89 (d, J=7.49 Hz, 1H),
7.40-7.36 (m, 2H), 7.23-7.16 (m, 4H), 7.08 (brs, 1H), 6.46 (d,
J=4.79 Hz, 1H), 6.01 (dd, J=13.26 Hz and 10.04 Hz, 1H), 5.80 (brs,
1H), 5.70 (d, J=7.49 Hz, 1H), 5.58 (brs, 1H), 4.88 (heptuplet,
J=6.26 Hz, 1H), 4.46-4.40 (m, 1H), 4.19-4.12 (m, 1H), 4.09-4.08 (m,
1H), 4.00-3.99 (m, 1H), 3.83-3.73 (m, 1H), 3.39-3.35 (m, 1H), 1.23
(d, J=7.02 Hz, 3H), 1.18 (d, J=6.33 Hz, 3H), 1.175 (d, J=6.33 Hz,
3H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 3.24 (s,
1P); MS (ESI) m/z=529.0 (MH.sup.+).
Example 2
Compound 102b
Ethyl
(2S)-2-[[[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydro-
xy-tetrahydrothiophen-2-yl]methoxy-(2-ethoxy-2-oxo-ethoxy)phosphoryl]amino-
]-4-methyl-pentanoate
##STR00039##
[0360] Compound 102b was synthesized according to Scheme 2 and to
general procedure B with reagent B2.
[0361] Compound 102b (diastereoisomer 1): white solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.89 (d, J=7.50 Hz, 1H), 7.17
(brs, 1H), 7.08 (brs, 1H), 6.45 (d, J=4.84 Hz, 1H), 5.76 (d, J=5.15
Hz, 1H), 5.71 (d, J=7.50 Hz, 1H), 5.66 (dd, J=12.94 Hz and 10.27
Hz, 1H), 5.55 (d, J=3.87 Hz, 1H), 4.49 (d, J=9.74 Hz, 1H),
4.51-4.43 (m, 1H), 4.37-4.31 (m, 1H), 4.16 (q, J=7.07 Hz, 2H),
4.12-4.04 (m, 4H), 4.00-3.97 (m, 1H), 3.76-3.67 (m, 1H), 3.38-3.36
(m, 1H), 1.78-1.68 (m, 1H), 1.53-1.38 (m, 2H), 1.22 (t, J=7.07 Hz,
3H), 1.20 (t, J=7.07 Hz, 3H), 0.90-0.86 (m, 6H); .sup.31P NMR
(DMSO-d.sub.6, 162 MHz) .delta. (ppm) 8.29 (s, 1P); MS (ESI)
m/z=567.5 (MH.sup.+).
[0362] Compound 102b (diastereoisomer 2): white solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.90 (d, J=7.45 Hz, 1H), 7.17
(brs, 1H), 7.08 (brs, 1H), 6.46 (d, J=4.88 Hz, 1H), 5.76 (d, J=5.06
Hz, 1H), 5.71 (d, J=7.54 Hz, 1H), 5.67 (dd, J=13.02 Hz and 10.20
Hz, 1H), 5.57 (d, J=3.94 Hz, 1H), 4.51-4.42 (m, 2H), 4.40-4.30 (m,
1H), 4.18-4.05 (m, 6H), 4.01-3.97 (m, 1H), 3.72-3.63 (m, 1H),
3.40-3.36 (m, 1H), 1.74-1.67 (m, 1H), 1.53-1.38 (m, 2H), 1.22 (t,
J=7.06 Hz, 3H), 1.19 (t, J=7.06 Hz, 3H), 0.90-0.87 (m, 6H);
.sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 8.17 (s, 1P); MS
(ESI) m/z=567.5 (MH.sup.+).
Example 3
Compound 103
4-amino-1-[(2R,3S,4S,5R)-5-[[(benzylamino)-[(5-nitro-2-furyl)methoxy]phosp-
horyl]oxymethyl]-3,4-dihydroxy-tetrahydrothiophen-2-yl]pyrimidin-2-one
##STR00040##
[0364] Compound 103 was synthesized according to Scheme 2 and to
general procedure B with reagent B3.
[0365] Compound 103 (diastereoisomer 1): solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.86 (d, J=7.53 Hz, 1H), 7.67
(d, J=3.77 Hz, 1H), 7.34-7.29 (m, 4H), 7.27-7.21 (m, 1H), 7.17
(brs, 1H), 7.08 (brs, 1H), 6.89 (d, J=3.77 Hz, 1H), 6.45 (d, J=4.90
Hz, 1H), 5.85-5.76 (m, 2H), 5.69 (d, J=7.53 Hz, 1H), 5.57 (d,
J=3.86 Hz, 1H), 5.04-4.93 (m, 2H), 4.37-4.31 (m, 1H), 4.08-3.97 (m,
5H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 9.94 (s,
1P); MS (ESI) m/z=554.4 (MH.sup.+).
[0366] Compound 103 (diastereoisomer 2): solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.88 (d, J=7.50 Hz, 1H), 7.67
(d, J=3.59 Hz, 1H), 7.32-7.29 (m, 4H), 7.27-7.21 (m, 1H), 7.17
(brs, 1H), 7.08 (brs, 1H), 6.89 (d, J=3.75 Hz, 1H), 6.45 (d, J=4.84
Hz, 1H), 5.85-5.78 (m, 1H), 5.77 (d, J=5.16 Hz, 1H), 5.71 (d,
J=7.50 Hz, 1H), 5.58 (d, J=3.97 Hz, 1H), 5.04-4.94 (m, 2H),
4.38-4.27 (m, 1H), 4.12-4.05 (m, 2H), 4.02-3.97 (m, 3H), 3.38-3.37
(m, 1H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 9.93
(s, 1P); MS (ESI) m/z=554.4 (MH.sup.+).
Example 4
Compound 104b
Methyl
(2S)-2-[[[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydr-
oxy-tetrahydrothiophen-2-yl]methoxy-(2-methoxy-2-oxo-ethoxy)phosphoryl]ami-
no]-4-methyl-pentanoate
##STR00041##
[0368] Compound 104b was synthesized according to Scheme 2 and to
general procedure B with reagent B4.
[0369] Compound 104b (diastereoisomer 1): solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.89 (d, J=7.47 Hz, 1H), 7.17
(brs, 1H), 7.08 (brs, 1H), 6.45 (d, J=4.78 Hz, 1H), 5.76 (d, J=5.09
Hz, 1H), 5.71 (d, J=7.47 Hz, 1H), 5.69 (dd, J=12.87 Hz and 10.28
Hz, 1H), 5.55 (d, J=4.00 Hz, 1H), 4.53-4.50 (m, 2H), 4.35-4.30 (m,
1H), 4.10-4.04 (m, 2H), 4.00-3.97 (m, 1H), 3.78-3.71 (m, 1H), 3.70
(s, 3H), 3.64 (s, 3H), 1.76-1.67 (m, 1H), 1.54-1.39 (m, 2H),
0.89-0.86 (m, 6H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta.
(ppm) 8.26 (s, 1P); MS (ESI) m/z=539.2 (MH.sup.+).
[0370] Compound 104b (diastereoisomer 2): solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.90 (d, J=7.46 Hz, 1H), 7.18
(brs, 1H), 7.08 (brs, 1H), 6.45 (d, J=4.98 Hz, 1H), 5.76 (d, J=5.11
Hz, 1H), 5.72 (d, J=7.46 Hz, 1H), 5.72 (dd, J=13.27 Hz and 10.09
Hz, 1H), 5.57 (d, J=4.01 Hz, 1H), 4.53-4.42 (m, 2H), 4.36-4.30 (m,
1H), 4.17-4.11 (m, 1H), 4.08-4.05 (m, 1H), 4.01-3.98 (m, 1H),
3.75-3.68 (m, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 1.75-1.65 (m, 1H),
1.54-1.38 (m, 2H), 0.88 (d, J=6.36 Hz, 3H), 0.87 (d, J=6.36 Hz,
3H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 8.13 (s,
1P); MS (ESI) m/z=539.2 (MH.sup.+).
Example 5
Compound 105
4-amino-1-[(2R,3S,4S,5R)-5-[[(benzylamino)-[2-(tert-butyldisulfanyl)ethoxy-
]phosphoryl]oxymethyl]-3,4-dihydroxy-tetrahydrothiophen-2-yl]pyrimidin-2-o-
ne
##STR00042##
[0372] Compound 105 was synthesized according to Scheme 2 and to
general procedure B with reagent B5.
[0373] Compound 105 (diastereoisomer 1): solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.88 (d, J=7.55 Hz, 1H),
7.36-7.30 (m, 4H), 7.27-7.22 (m, 2H), 7.11 (brs, 1H), 6.44 (d,
J=4.86 Hz, 1H), 5.76 (d, J=5.12 Hz, 1H), 5.70 (d, J=7.55 Hz, 1H),
5.70-5.63 (m, 1H), 5.57 (d, J=3.97 Hz, 1H), 4.34-4.28 (m, 1H),
4.09-3.97 (m, 7H), 3.38-3.36 (m, 1H), 2.92 (t, J=6.58 Hz, 2H), 1.30
(s, 9H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 9.61
(s, 1P); MS (ESI) m/z=577.0 (MH.sup.+).
[0374] Compound 105 (diastereoisomer 2): solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.90 (d, J=7.46 Hz, 1H),
7.35-7.30 (m, 4H), 7.28-7.22 (m, 1H), 7.18 (brs, 1H), 7.08 (brs,
1H), 6.45 (d, J=4.92 Hz, 1H), 5.76 (d, J=5.16 Hz, 1H), 5.71 (d,
J=7.46 Hz, 1H), 5.70-5.63 (m, 1H), 5.57 (d, J=4.01 Hz, 1H),
4.30-4.24 (m, 1H), 4.11-3.96 (m, 7H), 3.38-3.36 (m, 1H), 2.92 (t,
J=6.64 Hz, 2H), 1.29 (s, 9H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz)
.delta. (ppm) 9.57 (s, 1P); MS (ESI) m/z=577.0 (MH.sup.+).
Example 6
Compound 106b
4-amino-1-[(2R,3S,4S,5R)-4-[(benzylamino)-[(3-methyl-2-nitro-imidazol-4-yl-
)methoxy]phosphoryl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrothiophen-2-yl-
]pyrimidin-2-one
##STR00043##
[0376] Compound 106b was synthesized according to Scheme 2 and to
general procedure B with reagent B6.
[0377] Compound 106b: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
(ppm) 7.97 (d, J=7.22 Hz, 1H), 7.30-7.26 (m, 3H), 7.23-7.15 (m,
5H), 6.45 (d, J=5.51 Hz, 1H), 5.83 (d, J=4.86 Hz, 1H), 5.77-5.70
(m, 2H), 5.17 (t, J=5.51 z, 1H), 4.94-4.87 (m, 2H), 4.66-4.61 (m,
1H), 4.28-4.24 (m, 1H), 3.92-3.84 (m, 2H), 3.82-3.76 (m, 1H), 3.78
(s, 3H), 3.66-3.60 (m, 1H), 3.28-3.24 (m, 2H); .sup.31P NMR
(DMSO-d.sub.6, 162 MHz) .delta. (ppm) 9.35 (s, 1P); MS (ESI)
m/z=568.1 (MH.sup.+).
Example 6a
[0378] Compound 106a was synthesized according to Scheme 2 and to
general procedure B with reagent B6.
[0379] Preparation of Compound 107 and compound C2
[0380] Compound 107 was synthesized according to scheme 2 and to
the following general procedure C.
[0381] To a solution of compound A2 (3.38 mmol) and
2-(2,2-dimethyl-3-trityloxypropanoyl)-sulfanylethoxyphosphinic acid
(5.08 mmol) in pyridine (12 mL/mmol) at 0.degree. C. was slowly
added pivaloyl chloride (6.77 mmol). The reaction mixture was
stirred for 1 hour at 0.degree. C. and for 2 hours at room
temperature. The reaction was monitored by LC/MS. The reaction
mixture was quenched with a 1M solution of NH.sub.4Cl and extracted
with ethyl acetate. The organic layer was dried, filtered and
concentrated under reduced pressure to afford the expected
intermediate.
[0382] To a solution of this intermediate (1.1 mmol) in carbon
tetrachloride (20 mL/mmol) and DCM (15 mL/mmol) were added
benzylamine (5.5 mmol) and triethylamine (6.6 mmol) at room
temperature. The reaction mixture was stirred overweekend, and
then, concentrated under reduced pressure and purified by flash
chromatography on silica (DCM/methanol) to afford the expected
intermediate.
[0383] To a solution of this intermediate (0.49 mmol) in DCM (30
mL/mmol) was added trifluoroacetic acid (7.4 mmol) under nitrogen.
The reaction mixture was stirred at room temperature overnight and
purified by flash chromatography on silica (DCM/methanol: 0 to 20%)
followed by MS-preparative HPLC to afford the expected mixture of
diastereoisomers C2.
[0384] The compound C2 (0.35 mmol) was dissolved in a 7N ammonia
solution in methanol (50 mL/mmol) and the reaction mixture was
stirred at room temperature for 4 hours. The reaction mixture was
concentrated under reduced pressure and purified by RP-18
chromatography (H.sub.2O/CH.sub.3CN) followed by RP-18
chromatography (H.sub.2O+TEAB/CH.sub.3CN) to afford the expected
compound as solid.
[0385] Compound C2:
S-[2-[[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-tetra-
hydrothiophen-2-yl]methoxy-(benzylamino)phosphoryl]oxyethyl]
3-hydroxy-2,2-dimethyl-propanethioate:
[0386] .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 9.51 (s,
0.5P), 9.48 (s, 0.5P); MS (ESI) m/z=589.0 (MH.sup.+).
Example 7
Compound 107
[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydroth-
iophen-2-yl]methoxy-N-benzyl-phosphonamidic acid
##STR00044##
[0388] Compound 107: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
(ppm) 7.93 (d, J=7.50 Hz, 1H), 7.35-7.33 (m, 2H), 7.29-7.25 (m,
2H), 7.19-7.15 (m, 2H), 7.04 (brs, 1H), 6.37 (d, J=5.27 Hz, 1H),
6.24 (brs, 1H), 5.92 (brs, 1H), 5.71 (d, J=7.49 Hz, 1H), 4.26 (t,
J=4.21 Hz, 1H), 4.07-4.00 (m, 1H), 3.95 (t, J=5.05 Hz, 1H), 3.90
(d, J=9.38 Hz, 2H), 3.75-3.68 (m, 1H), 3.27-3.23 (m, 1H); .sup.31P
NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 6.72 (s, 1P); MS (ESI)
m/z=429.0 (MH.sup.+).
Example 7a
Compound C2
S-[2-[[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-tetrah-
ydrothiophen-2-yl]methoxy-(benzylamino)phosphoryl]oxyethyl]
3-hydroxy-2,2-dimethyl-propanethioate
[0389] Compound C2: .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta.
(ppm) 9.51 (s, 0.5P), 9.48 (s, 0.5P); MS (ESI) m/z=589.0
(MH.sup.+).
##STR00045##
Example 8
Compound 108b
[(2S)-2-[[(4aR,6R,7S,7aS)-6-(4-amino-2-oxo-pyrimidin-1-yl)-7-hydroxy-2-oxo-
-4a,6,7,7a-tetrahydro-4H-thieno[3,2-d][1,3,2]dioxaphosphinin-2-yl]amino]pr-
opyl] acetate
##STR00046##
[0391] To a suspension of compound A2 (1.32 mmol) in DCM (25
mL/mmol) were added dropwise a solution of compound D2 (1.59 mmol)
in THF (10 mL/mmol) and then a solution of
1,8-diazabicyclo[5.4.0]undec-7-ene (3.12 mmol) in acetonitrile (25
mL/mmol). The reaction mixture was stirred at room temperature
under nitrogen for 1 day. The reaction mixture was diluted with DCM
and washed 5 times with a saturated aqueous NaHCO.sub.3 solution.
The aqueous layer was re-extracted once with DCM. Combined organic
layers were dried, filtered and concentrated under reduced
pressure. The crude residue was purified by flash chromatography on
silica gel (DCM/MeOH) to afford the expected intermediate compound
as a solid. This compound was dissolved in anhydrous DCM (10
mL/mmol) under nitrogen and trifluoroacetic acid (0.8 mL/mmol) was
added. The reaction mixture was stirred at room temperature for 3
h, then the mixture was concentrated to 1/3 of solvent volume and
loaded onto a PE-AX cartridge to scavenge TFA. The target compound
was eluted with acetonitrile and concentrated under reduced
pressure. The crude residue was purified twice by flash
chromatography on silica (DCM/MeOH) to afford the expected compound
as a solid as a single diastereoisomer.
[0392] Compound 108b (1 diastereoisomer): .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.85 (d, J=7.39 Hz, 1H), 7.23
(brs, 1H), 7.15 (brs, 1H), 6.42 (d, J=8.35 Hz, 1H), 6.03 (d, J=5.64
Hz, 1H), 5.77 (d, J=7.39 Hz, 1H), 5.55 (dd, J=13.53 Hz and 10.03
Hz, 1H), 4.57-4.52 (m, 1H), 4.47-4.36 (m, 2H), 4.33-4.27 (m, 1H),
3.88-3.80 (m, 2H), 3.47-3.40 (m, 1H), 2.00 (s, 3H), 1.06 (d, J=6.58
Hz, 3H); .sup.31P NMR (DMSO-d.sub.6, 162 MHz) .delta. (ppm) 5.39
(s, 1P); MS (ESI) m/z=421.0 (MH.sup.+).
Example 9
In Vitro Inhibition
[0393] Materials
[0394] Cells were grown in RPMI-1640 supplemented with L-Glutamine
and 10% FBS of the following cell lines:
[0395] CCRF-CEM; CCRF-CEM-cytarabine resistant; HL-60; K562;
CFPAC-1; MiaPACA-2; BxPC-3; PANC-1; HepG2; MDA-MB-231; HCT-116;
A498; and NCI-H69
[0396] Method
[0397] 18, 96 well plates of each cell line were seeded with the
optimized number of cells per well in a total volume of 50 .mu.L
per well. The plates were left overnight. Plate wells were seeded
with 100 .mu.L media for media control. The following day, cells
were exposed to test compounds as described below. At the same time
as drug exposure, a CTG assay was conducted on the 18.sup.th plate
for the 0 hr count.
[0398] The compounds were added to cells and medium already on the
plate to give desired final concentrations. 50 .mu.L media were
added to cell control wells, and 50 .mu.L of mix added to vehicle
control wells. 10 .mu.M Doxorubicin was added to appropriate wells.
Cells exposed to test compound were incubated at 37.degree. C. for
72 hr followed by a CTG assay.
[0399] CellTiter-Glo (CTG)
[0400] At the end of the 72 hr exposure period, plates were removed
for a CellTiter-Glo (CTG) assay from a 37.degree. C., 5% CO.sub.2
incubator and placed on the bench at room temperature for 30 mins.
100 .mu.L of CellTiter-Glo reagent was added and mixed for 2 mins,
followed by a further 10 min incubation at room temperature.
Luminescence was recorded using Synergy 4.0.
[0401] All the exemplified compounds were tested in accordance with
this method and were found to have IC.sub.50 values of less than
100 .mu.M at each cell line. The results for compounds are provided
in Tables 1 and 2.
TABLE-US-00001 TABLE 1 In vitro inhibition of CCRF-CEM;
CCRF-CEM-cytarabine resistant; HL-60; K562; CFPAC-1; MiaPACA-2; and
BxPC-3 CCRF-CEM- cytarabine CCRF-CEM resistant HL-60 K562 CFPAC-1
MiaPACA-2 BxPC-3 Compound IC.sub.50(.mu.M) 101b A C B C C C C
(diastereoisomer 1) 101b A B B C C B C (diastereoisomer 2) 102b A C
B C C C C (diastereoisomer 1) 102b A C B C C C C (diastereoisomer
2) 103 A B A B C B C (diastereoisomer 1) 103 A B A B B B B
(diastereoisomer 2) 104b A C B C C C C (diastereoisomer 1) 104b A C
A C C C C (diastereoisomer 2) 105 B C B C C B C (diastereoisomer 1)
105 C C C C C B C (diastereoisomer 2) 106b C C C C C C C (mixture
of diastereoisomers) 107 B C B C C B C 108b C C C C C C C
(diastereoisomer 1)
TABLE-US-00002 TABLE 2 In vitro inhibition of PANC-1; HepG2;
MDA-MB-231; HCT-116; A498; and NCI-H69 PANC-1 HepG2 MDA-MB-231
HCT-116 A498 NCI-H69 Compound IC.sub.50(.mu.M) 101b C C C C C C
(diastereoisomer 1) 101b C B C B C C (diastereoisomer 2) 102b C B C
C C C (diastereoisomer 1) 102b C C C C C C (diastereoisomer 2) 103
C B C C C C (diastereoisomer 1) 103 C B C B B B (diastereoisomer 2)
104b C B C C C C (diastereoisomer 1) 104b C C C C C C
(diastereoisomer 2) 105 C C C C C B (diastereoisomer 1) 105 C C C C
C C (diastereoisomer 2) 106b C C C C C C (mixture of
diastereoisomers) 107 C B C C C C 108b C C C C C C (diastereoisomer
1)
[0402] The IC.sub.50 values in Tables 1 and 2 are as follows:
[0403] A=<1 .mu.M
[0404] B=.gtoreq.1 and 10.ltoreq..mu.M
[0405] C=>10 and .ltoreq.100 .mu.M
[0406] The ex-vivo effect of the compounds on AML samples when the
plates were incubated for 48 hours is illustrated in Table 3:
TABLE-US-00003 Compound EC.sub.50 abs. (.mu.M) Emax (%)
##STR00047## Diastereomer 1 D A ##STR00048## Diastereomer 2 C A
##STR00049## B B ##STR00050## Diastereomer 1 C A ##STR00051##
Diastereomer 2 C A ##STR00052## Diastereomer 1 C A ##STR00053##
Diastereomer 2 B A ##STR00054## Diastereomer 1 B A ##STR00055##
Diastereomer 2 B A ##STR00056## D C ##STR00057## Diastereomer 1 D B
##STR00058## Diastereomer 2 D C
[0407] EC.sub.50 values are provided as follows:
[0408] A.ltoreq.1 .mu.M, 1<B.ltoreq.10 .mu.M, 10<C<20
.mu.M, D.gtoreq.20 .mu.M;
[0409] Emax values are provided as follows:
[0410] A=0-10%; B=10-20%; C>20%
* * * * *